ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Arzerra 100 mg concentrate for solution for infusion.
2.
One ml of concentrate contains 20 mg of ofatumumab.
Each vial contains 100 mg of ofatumumab in 5 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.
3.
Concentrate for solution for infusion (sterile concentrate).
Clear to slightly opalescent, colourless liquid. Visible particles may be present.
4.
Arzerra is indicated for the treatment of chronic lymphocytic leukaemia (CLL) in patients who are
refractory to fludarabine and alemtuzumab.
4.2
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:
Infusion number
(dose)
Intravenous corticosteroid dose Analgesic dose
Antihistamine dose
1 (300 mg)
Equivalent to 100 mg
prednisolone
Equivalent to 1,000 mg
paracetamol
Equivalent to 10 mg
cetirizine
2 (2,000 mg)
Equivalent to 100 mg
prednisolone
Equivalent to 1,000 mg
paracetamol
Equivalent to 10 mg
cetirizine
3-8 (2,000 mg)
Equivalent to 0-100 mg
prednisolone
a)
Equivalent to 1,000 mg
paracetamol
Equivalent to 10 mg
cetirizine
9
(2,000 mg)
Equivalent to 100 mg
prednisolone
Equivalent to 1,000 mg
paracetamol
Equivalent to 10 mg
cetirizine
10-12 (2,000 mg) Equivalent to 50-100 mg
prednisolone
b)
Equivalent to 1,000 mg
paracetamol
Equivalent to 10 mg
cetirizine
2
a)
If the second infusion is completed without a severe adverse drug reaction, the dose may be reduced
at the discretion of the physician.
b)
If the ninth infusion is completed without a serious adverse drug reaction, the dose may be reduced
at the discretion of the physician.
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)
.
3
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/mm
3
),
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.
4
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.
5
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.
MedDRA System
Organ Class
Very common
Common
Uncommon
Infections and
Infestations
Lower respiratory
tract infection,
including pneumonia,
upper respiratory tract
infection
Sepsis, including neutropenic
sepsis and septic shock,
herpes virus infection,
urinary tract infection
Blood and
lymphatic system
disorders
Neutropenia, anaemia Febrile neutropenia,
thrombocytopenia,
leukopenia
Agranulocytosis,
coagulopathy, red cell
aplasia, lymphopenia
Immune system
disorders
Anaphylactoid reactions,
hypersensitivity
Metabolism and
nutrition disorders
Tumour lysis
syndrome
Cardiac disorders
Tachycardia
Vascular disorders
Hypotension, hypertension
Respiratory,
thoracic and
mediastinal
disorders
Bronchospasm, hypoxia,
dyspnoea, chest discomfort,
pharyngolaryngeal pain,
cough, nasal congestion
Gastrointestinal
disorders
Small bowel obstruction,
diarrhoea, nausea
Skin and
subcutaneous tissue
disorders
Rash
Urticaria, pruritus, flushing
Musculoskeletal and
connective tissue
disorders
Back pain
General disorders
and administration
site conditions
Cytokine release syndrome,
pyrexia, rigors, chills,
hyperhidrosis, fatigue
6
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.
4.9
No case of overdose has been reported.
5.
5.1 Pharmacodynamic properties
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).
7
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
(Primary) endpoint
1
Patients refractory to fludarabine and
alemtuzumab
n = 59
Overall response rate
Responders, n (%)
34 (58)
Response rate in patients with prior rituximab therapy
Responders, n (%)
19/35 (54)
95% CI (%)
37, 71
Response rate in patients with chromosomal abnormality
17p deletion
Responders, n (%)
7/17 (41)
11q deletion
18, 67
Responders, n (%)
15/24 (63)
95% CI (%)
41, 81
Median overall survival
Months
13.7
95% CI
9.4, non-estimable
Progression-free survival
Months
5.7
95% CI
4.5, 8.0
8
99% CI (%)
40, 74
95% CI (%)
Median duration of response
Months
7.1
95% CI 3.7, 7.6
Median time to next CLL therapy
Months
9.0
95% CI 7.3, 10.7
1
The overall response was assessed by an Independent Response Committee using the 1996 National
Cancer Institute Working Group (NCIWG) guidelines for 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
Efficacy endpoint or haematological parameter
a
Subjects with benefit/subjects with abnormality at
baseline (%)
Patients refractory to fludarabine and alemtuzumab
Lymphocyte count
Normalisation (≤4x10
9
/l)
31/42 (74)
Complete resolution of constitutional
symptoms
b
15/31 (48)
Lymphadenopathy
c
≥50% improvement
34/55 (62)
Complete resolution
9/55 (16)
Splenomegaly
≥50% improvement
16/30 (53)
Complete resolution
14/30 (47)
Hepatomegaly
≥50% improvement
11/18 (61)
Complete resolution
9/18 (50)
Haemoglobin <11 g/dl at baseline to >11 g/dl
post baseline
8/26 (31)
Platelet counts <100x10
9
/l at baseline to >50%
increase or >100x10
9
/l post baseline
12/29 (41)
Neutrophils <1x10
9
/l at baseline to ≥1.5x10
9
/l 1/19 (5)
a
Excludes subject visits from date of first transfusion, treatment with erythropoietin, or
treatment with growth factors. For subjects with missing baseline data, latest screening/unscheduled
data was carried forward to baseline.
b
Complete resolution of constitutional symptoms (fever, night sweats, fatigue, weight loss)
defined as the presence of any symptoms at baseline, followed by no symptoms present.
c
Lymphadenopathy measured by sum of the products of greatest diameters (SPD) as assessed
by physical examination.
Arzerra was also given to a group of patients (n=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,
9
≥50% decrease
20/42 (48)
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).
5.2 Pharmacokinetic properties
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.
10
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.
5.3 Preclinical safety data
Preclinical data reveal no special hazards for humans.
Intravenous and subcutaneous administration to monkeys resulted in the expected depletion of
peripheral and lymphoid tissue B cell counts with no associated toxicological findings. As anticipated,
a reduction in the IgG humoral immune response to keyhole limpet haemocyanin was noted, but there
were no effects on delayed-type hypersensitivity responses. In a few animals, increased red cell
destruction occurred presumably as a result of monkey anti-drug antibodies
coating the red cells. A
corresponding increase in reticulocyte counts seen in these monkeys was indicative of a regenerative
response in the bone marrow.
Intravenous administration of ofatumumab to pregnant cynomolgus monkeys at 100 mg/kg once
weekly from days 20 to 50 of gestation did not elicit maternal or foetal toxicity or teratogenicity. At
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.
11
6.
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
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.
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 of the diluted medicinal product, see section 6.3.
6.5 Nature and contents of container
Clear Type I glass vial with a latex-free bromobutyl rubber stopper and aluminium over-seal,
containing 5 ml of concentrate for solution for infusion.
Arzerra is available in packs of 3 vials and it is supplied with two extension sets.
6.6 Special precautions for disposal and other handling
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.
12
•
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.
300 mg dose
- Use 3 vials (15 ml total, 5 ml per vial):
-
withdraw and discard 15 ml from a 1,000 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 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
Time (minutes)
ml/hour
0 – 30
12
31 – 60
25
61 – 90
50
91 – 120
100
121 +
200
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:
13
Infusions 3 to 12: schedule
Time (minutes)
ml/hour
0 – 30
25
31 – 60
50
61 – 90
100
91 – 120
200
121 +
400
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.
7.
Glaxo Group Ltd
Glaxo Wellcome House
Berkeley Avenue
Greenford
Middlesex
UB6 0NN
United Kingdom
8.
EU/1/10/625/001
9.
Date of first authorisation: 19/04/2010
Date of last renewal: 21/04/2011
Detailed information on this medicinal product is available on the website of the European Medicines
Agency (EMA)
http://www.ema.europa.eu
/.
14
1.
Arzerra 1,000 mg concentrate for solution for infusion.
2.
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.
3.
Concentrate for solution for infusion (sterile concentrate).
Clear to slightly opalescent, colourless liquid. Visible particles may be present.
4.
Arzerra is indicated for the treatment of chronic lymphocytic leukaemia (CLL) in patients who are
refractory to fludarabine and alemtuzumab.
4.2
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:
Infusion number
(dose)
Intravenous corticosteroid dose
Analgesic dose
Antihistamine dose
1 (300 mg)
Equivalent to 100 mg
prednisolone
Equivalent to 1,000 mg
paracetamol
Equivalent to 10 mg
cetirizine
2 (2,000 mg)
Equivalent to 100 mg
prednisolone
Equivalent to 1,000 mg
paracetamol
Equivalent to 10 mg
cetirizine
3-8 (2,000 mg)
Equivalent to 0-100 mg
prednisolone
a)
Equivalent to 1,000 mg
paracetamol
Equivalent to 10 mg
cetirizine
9
(2,000 mg)
Equivalent to 100 mg
prednisolone
Equivalent to 1,000 mg
paracetamol
Equivalent to 10 mg
cetirizine
10-12 (2,000 mg) Equivalent to 50-100 mg
prednisolone
b)
Equivalent to 1,000 mg
paracetamol
Equivalent to 10 mg
cetirizine
15
a)
If the second infusion is completed without a severe adverse drug reaction, the dose may be reduced
at the discretion of the physician.
b)
If the ninth infusion is completed without a serious adverse drug reaction, the dose may be reduced
at the discretion of the physician.
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)
.
16
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/mm
3
),
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.
17
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.
18
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.
MedDRA System
Organ Class
Very common
Common
Uncommon
Infections and
Infestations
Lower respiratory
tract infection,
including pneumonia,
upper respiratory tract
infection
Sepsis, including neutropenic
sepsis and septic shock,
herpes virus infection,
urinary tract infection
Blood and
lymphatic system
disorders
Neutropenia, anaemia Febrile neutropenia,
thrombocytopenia,
leukopenia
Agranulocytosis,
coagulopathy, red cell
aplasia, lymphopenia
Immune system
disorders
Anaphylactoid reactions,
hypersensitivity
Metabolism and
nutrition disorders
Tumour lysis
syndrome
Cardiac disorders
Tachycardia
Vascular disorders
Hypotension, hypertension
Respiratory,
thoracic and
mediastinal
disorders
Bronchospasm, hypoxia,
dyspnoea, chest discomfort,
pharyngolaryngeal pain,
cough, nasal congestion
Gastrointestinal
disorders
Small bowel obstruction,
diarrhoea, nausea
Skin and
subcutaneous tissue
disorders
Rash
Urticaria, pruritus, flushing
Musculoskeletal and
connective tissue
disorders
Back pain
General disorders
and administration
site conditions
Cytokine release syndrome,
pyrexia, rigors, chills,
hyperhidrosis, fatigue
19
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.
4.9
No case of overdose has been reported.
5.
5.1 Pharmacodynamic properties
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).
20
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
(Primary) endpoint
1
Patients refractory to fludarabine and
alemtuzumab
n = 59
Overall response rate
Responders, n (%)
34 (58)
Response rate in patients with prior rituximab therapy
Responders, n (%)
19/35 (54)
95% CI (%)
37, 71
Response rate in patients with chromosomal abnormality
17p deletion
Responders, n (%)
7/17 (41)
11q deletion
18, 67
Responders, n (%)
15/24 (63)
95% CI (%)
41, 81
Median overall survival
Months
13.7
95% CI
9.4, non-estimable
Progression-free survival
Months
5.7
95% CI
4.5, 8.0
21
99% CI (%)
40, 74
95% CI (%)
Median duration of response
Months
7.1
95% CI 3.7, 7.6
Median time to next CLL therapy
Months
9.0
95% CI 7.3, 10.7
1
The overall response was assessed by an Independent Response Committee using the 1996 National
Cancer Institute Working Group (NCIWG) guidelines for 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
Efficacy endpoint or haematological parameter
a
Subjects with benefit/subjects with abnormality at
baseline (%)
Patients refractory to fludarabine and alemtuzumab
Lymphocyte count
Normalisation (≤4x10
9
/l)
31/42 (74)
Complete resolution of constitutional
symptoms
b
15/31 (48)
Lymphadenopathy
c
≥50% improvement
34/55 (62)
Complete resolution
9/55 (16)
Splenomegaly
≥50% improvement
16/30 (53)
Complete resolution
14/30 (47)
Hepatomegaly
≥50% improvement
11/18 (61)
Complete resolution
9/18 (50)
Haemoglobin <11 g/dl at baseline to >11 g/dl
post baseline
8/26 (31)
Platelet counts <100x10
9
/l at baseline to >50%
increase or >100x10
9
/l post baseline
12/29 (41)
Neutrophils <1x10
9
/l at baseline to ≥1.5x10
9
/l 1/19 (5)
a
Excludes subject visits from date of first transfusion, treatment with erythropoietin, or
treatment with growth factors. For subjects with missing baseline data, latest screening/unscheduled
data was carried forward to baseline.
b
Complete resolution of constitutional symptoms (fever, night sweats, fatigue, weight loss)
defined as the presence of any symptoms at baseline, followed by no symptoms present.
c
Lymphadenopathy measured by sum of the products of greatest diameters (SPD) as assessed
by physical examination.
Arzerra was also given to a group of patients (n=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,
22
≥50% decrease
20/42 (48)
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).
5.2 Pharmacokinetic properties
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.
23
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.
5.3 Preclinical safety data
Preclinical data reveal no special hazards for humans.
Intravenous and subcutaneous administration to monkeys resulted in the expected depletion of
peripheral and lymphoid tissue B cell counts with no associated toxicological findings. As anticipated,
a reduction in the IgG humoral immune response to keyhole limpet haemocyanin was noted, but there
were no effects on delayed-type hypersensitivity responses. In a few animals, increased red cell
destruction occurred presumably as a result of monkey anti-drug antibodies
coating the red cells. A
corresponding increase in reticulocyte counts seen in these monkeys was indicative of a regenerative
response in the bone marrow.
Intravenous administration of ofatumumab to pregnant cynomolgus monkeys at 100 mg/kg once
weekly from days 20 to 50 of gestation did not elicit maternal or foetal toxicity or teratogenicity. At
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.
24
6.
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
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.
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 of the diluted medicinal product, see section 6.3.
6.5 Nature and contents of container
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.
6.6 Special precautions for disposal and other handling
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.
25
•
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
Time (minutes)
ml/hour
0 – 30
12
31 – 60
25
61 – 90
50
91 – 120
100
121 +
200
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:
26
Infusions 3 to 12: schedule
Time (minutes)
ml/hour
0 – 30
25
31 – 60
50
61 – 90
100
91 – 120
200
121 +
400
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.
7.
Glaxo Group Ltd
Glaxo Wellcome House
Berkeley Avenue
Greenford
Middlesex
UB6 0NN
United Kingdom
8.
EU/1/10/625/003
9.
Date of first authorisation: 19/04/2010
Date of last renewal: 21/04/2011
Detailed information on this medicinal product is available on the website of the European Medicines
Agency (EMA)
http://www.ema.europa.eu
/.
27
ANNEX II
A.
MANUFACTURERS OF THE BIOLOGICAL ACTIVE
SUBSTANCE AND MANUFACTURING AUTHORISATION
HOLDER RESPONSIBLE FOR BATCH RELEASE
B. CONDITIONS OF THE MARKETING AUTHORISATION
C.
28
A. MANUFACTURERS OF THE BIOLOGICAL ACTIVE SUBSTANCE AND
MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturers of the biological active substance
Lonza Biologics plc
228 Bath Road
Slough, Berks SL1 4DX
United Kingdom
Lonza Biologicals, Inc.
101 International Drive
Portsmouth, NH 03801-2815
United States
Name and address of the manufacturer responsible for batch release
Glaxo Operations UK Ltd.
Harmire Road
Barnard Castle
Durham, DL12 8DT
United Kingdom
B. CONDITIONS OF THE MARKETING AUTHORISATION
•
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product
Characteristics, section 4.2).
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable.
•
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, presented in Module 1.8.1. of the
Marketing Authorisation, is in place and functioning before and whilst the product is on the market.
Risk Management Plan
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in
the Pharmacovigilance Plan, as agreed in version 1.4 of the Risk Management Plan (RMP) presented
in Module 1.8.2. of the Marketing Authorisation Application and any subsequent updates of the RMP
agreed by the CHMP.
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, the
updated RMP should be submitted at the same time as the next Periodic Safety Update Report
(PSUR).
29
In addition, an updated RMP should be submitted
⋅
When new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimisation activities
⋅
Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being reached
⋅
At the request of the European Medicines Agency
C. SPECIFIC OBLIGATIONS TO BE FULFILLED BY THE MARKETING
AUTHORISATION HOLDER
The Marketing Authorisation Holder shall complete the following programme of studies within the
specified time frame, the results of which shall form the basis of the annual reassessment of the
benefit/risk profile.
Clinical aspects
1. To conduct an open label, multicenter study investigating the safety and efficacy of ofatumumab
therapy versus physicians’ choice in patients with bulky fludarabine refractory chronic lymphocytic
leukaemia (CLL). The study report is to be submitted by December 2014.
2. To conduct a phase IV observational study to provide further data on the clinical efficacy and safety
of ofatumumab. The final protocol will be submitted for CHMP agreement within 3 months of
conditional marketing authorisation date. The time needed to recruit the target number of subjects
(100) will depend on the date of availability on the market of Arzerra across EU, degree of use and on
the willingness of patients and physicians to participate in the study. The study report is to be
submitted by June 2013.
30
ANNEX III
LABELLING AND PACKAGE LEAFLET
31
A. LABELLING
32
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON
1.
Arzerra 100 mg concentrate for solution for infusion
Ofatumumab
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
One ml contains 20 mg ofatumumab.
Each vial contains 100 mg ofatumumab in 5 ml.
3.
LIST OF EXCIPIENTS
Arginine, sodium acetate (E262), sodium chloride, polysorbate 80 (E433), edetate disodium (E386),
hydrochloric acid (E507), water for injections.
4.
Concentrate for solution for infusion.
100 mg/5 ml
3 vials x 5 ml
2 extension sets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Intravenous use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
33
9.
SPECIAL STORAGE CONDITIONS
Store and transport refrigerated.
Do not freeze.
Keep the vial in the outer carton in order to protect from light.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
11.
Glaxo Group Ltd, Glaxo Wellcome House, Berkeley Avenue, Greenford, Middlesex UB6 0NN,
United Kingdom
12.
EU/1/10/625/001
13.
BATCH NUMBER
Batch
14.
GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15.
INSTRUCTIONS ON USE
16.
INFORMATION IN BRAILLE
Justification for not including Braille accepted.
34
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
VIAL LABEL
1.
Arzerra
100 mg sterile concentrate
Ofatumumab
Intravenous use
2.
METHOD OF ADMINISTRATION
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Batch
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
100 mg/5 ml
6.
OTHER
35
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON
1.
Arzerra 1,000 mg concentrate for solution for infusion
Ofatumumab
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
One ml contains 20 mg ofatumumab.
Each vial contains 1,000 mg ofatumumab in 50 ml.
3.
LIST OF EXCIPIENTS
Arginine, sodium acetate (E262), sodium chloride, polysorbate 80 (E433), edetate disodium (E386),
hydrochloric acid (E507), water for injections.
4.
Concentrate for solution for infusion.
1,000 mg/50 ml
1 vial x 50 ml
2 extension sets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Intravenous use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
36
9.
SPECIAL STORAGE CONDITIONS
Store and transport refrigerated.
Do not freeze.
Keep the vial in the outer carton in order to protect from light.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
11.
Glaxo Group Ltd, Glaxo Wellcome House, Berkeley Avenue, Greenford, Middlesex UB6 0NN,
United Kingdom
12.
EU/1/10/625/003
13.
BATCH NUMBER
Batch
14.
GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15.
INSTRUCTIONS ON USE
16.
INFORMATION IN BRAILLE
Justification for not including Braille accepted.
37
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
VIAL LABEL
1.
Arzerra
1,000 mg sterile concentrate
Ofatumumab
Intravenous use
2.
METHOD OF ADMINISTRATION
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Batch
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
1,000 mg/50 ml
6.
OTHER
38
B. PACKAGE LEAFLET
39
PACKAGE LEAFLET: INFORMATION FOR THE USER
Arzerra 100 mg concentrate for solution for infusion
Arzerra 1,000 mg concentrate for solution for infusion
Ofatumumab
Read all of this leaflet carefully before you start using this medicine.
-
Keep this leaflet. You may need to read it again.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor.
In this leaflet
:
1.
What Arzerra is and what it is used for
2.
Before you are given Arzerra
3.
How Arzerra is given
5.
How to store Arzerra
6.
Further information
1.
WHAT ARZERRA IS AND WHAT IT IS USED FOR
Arzerra contains
ofatumumab,
which belongs to a group of medicines called
monoclonal antibodies
.
Arzerra is used to treat chronic lymphocytic leukaemia
(CLL). CLL is a cancer of the blood which
affects a type of white blood cell called
lymphocytes
. The lymphocytes multiply too quickly and live
too long, so there are too many of them circulating in your blood. The disease can also affect other
organs in your body. The antibody in Arzerra recognises a substance on the surface of lymphocytes
and causes the lymphocyte to die.
Arzerra is used to treat CLL in patients who have not responded to other types of chemotherapy or
treatments.
2.
BEFORE YOU ARE GIVEN ARZERRA
You must not receive Arzerra:
•
if you are allergic
(hypersensitive)
to ofatumumab or to any of the other ingredients of Arzerra
(listed in Section 6 ‘Further information’)
Î
Check with your doctor
if you think this may apply to you.
Take special care with Arzerra
Before you are given Arzerra your doctor needs to know:
•
if you have had
heart problems,
•
if you have
lung disease,
•
if you have 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.
Î
Check with your doctor
if you think any of these may apply to you
.
You may need extra
check-ups while you are being treated with Arzerra.
40
-
If you have any further questions, ask your doctor.
4.
Possible side effects
Vaccination and Arzerra
If you are having any vaccinations tell your doctor, or the person giving you the vaccine, that you are
being treated with Arzerra. Your response to the vaccine may be weakened and you may not be fully
protected.
Infusion reactions
Medicines of this type (
monoclonal antibodies
) can cause infusion reactions when they are injected
into the body. You will be given medicines such as anti-histamines, steroids or pain relievers to help
reduce any reaction. See also
Section 4, ‘Possible side effects’
.
If you think you have had a similar reaction before,
tell your doctor before you are given
Arzerra
.
Progressive multifocal leukoencephalopathy (PML)
Progressive multifocal leukoencephalopathy (PML), a serious and life threatening brain condition, has
been reported with medicines like Arzerra.
Tell your doctor immediately
if you have memory loss,
trouble thinking, difficulty with walking or loss of vision. If you had these symptoms prior to
treatment with Arzerra,
tell your doctor immediately
about any changes in these symptoms.
Other medicines and Arzerra
Tell your doctor
if you are taking any other medicines, if you’ve taken any recently, or if you start
taking new ones. This includes herbal medicines and other medicines you can obtain without a
prescription.
Pregnancy and breast-feeding
Arzerra is not usually recommended for use during pregnancy.
There is no information about the
safety of Arzerra in pregnant women.
•
Tell your doctor if you are pregnant
or planning to become pregnant. Your doctor will weigh
up the benefit to you against the risk to your baby of taking Arzerra while you're pregnant.
•
Use a reliable method of contraception
to avoid becoming
pregnant while you’re being
treated with Arzerra, and
for 12 months
after your last treatment.
•
If you do become pregnant during treatment with Arzerra
, tell your doctor
It is not known whether the ingredients in Arzerra pass into human milk.
Breast-feeding is not
recommended
during treatment with Arzerra
and
for 12 months
after the last time you were treated
with Arzerra.
Driving and using machines
Arzerra is unlikely to affect your ability to drive or use machines
Arzerra contains sodium
Arzerra contains 34.8 mg sodium in each 300 mg dose and 232 mg sodium in each 2,000 mg dose.
You need to take this into account if you are on a controlled sodium diet.
3.
HOW ARZERRA IS GIVEN
If you have any questions on the use of Arzerra, ask the doctor who is giving you the infusion.
41
The usual dose
The usual dose of Arzerra for the first infusion is 300 mg. This dose will be increased, usually to
2,000 mg, for the remaining infusions.
How it is given
Arzerra is given into a vein (
intravenously
) as an infusion (a drip) over several hours.
You will usually have a course of 12 infusions.
You will be given an infusion once a week for eight
weeks. This is followed by a four- to five-week gap. The remaining infusions will then be given once a
month for four months.
Medicines given before each infusion
Before each infusion of Arzerra, you will be given
pre-medication
- medicines which help to reduce
any infusion reactions. These may include anti-histamines, steroids and pain relievers. You will be
checked closely and if you do have any reactions these will be treated.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Arzerra can cause side effects, although not everybody gets them.
Infusion reactions
Medicines of this type (
monoclonal antibodies
) can cause infusion reactions, which are occasionally
severe. They are more likely during the first treatment.
Very common symptoms of an infusion reaction
(may affect more than 1 in 10 people):
•
skin rash
Common symptoms of an infusion reaction
(may affect up to 1 in 10 people):
•
allergic reactions, sometimes severe with swelling of face or mouth causing difficulty in
breathing (
anaphylactoid reactions
)
•
difficulty in breathing, shortness of breath, chest tightness, cough
•
low blood pressure (can cause light-headedness when you stand up)
•
flushing, high temperature
•
excessive sweating
•
shaking or shivering
•
rapid heart beat
•
feeling sick (
nausea
)
•
diarrhoea
•
back pain
•
high blood pressure
•
itchy, bumpy rash (
hives
)
•
throat pain or irritation
•
lack of energy
•
blocked nose.
Tell your doctor or a nurse immediately if you get any of these symptoms.
Very common side effects
These may affect
more than 1 in 10 people
:
•
infections of the lungs or airways (
respiratory tract
) such as pneumonia
•
infections of the ear, nose or throat
Very common side effects that may show up in your blood tests:
•
low levels of white blood cells
•
low levels of red blood cells (anaemia)
42
Common side effects
These may affect
up to 1 in 10 people
:
•
a fever due to an infection and low levels of white blood cells
•
blood infections
•
urinary tract infections
•
shingles
•
cold sores
•
blockage in the gut (
intestine
), which may feel like stomach pain.
Î
If you have persistent stomach pain,
see your doctor as soon as possible.
Common side effects that may show up in your blood tests:
•
low levels of platelets in the blood (cells that help blood to clot)
Uncommon side effects
These may affect
up to 1 in 100 people
:
•
increase in potassium, phosphate and uric acid in the blood that can cause kidney problems
(
tumour lysis syndrome
)
The symptoms of this condition include:
•
producing less urine than normal
•
muscle spasms.
Î
If you notice these symptoms,
contact your doctor as soon as possible
.
Uncommon side effects that may show up in your blood tests:
•
problems with blood clotting
•
the bone marrow failing to produce enough red or white blood cells
If you get side effects
Î
Tell your doctor
if any of the side effects you experience become
severe or troublesome, or if
you notice any side effects not listed in this leaflet.
5.
HOW TO STORE ARZERRA
Keep out of the reach and sight of children.
Do not use ofatumumab after the expiry date which is stated on the carton and vial label. The expiry
date refers to the last day of that month.
Store and transport refrigerated (2 °C – 8 °C).
Do not freeze.
Keep the vial in the outer carton in order to protect from light.
Store the diluted infusion solution between 2 °C and 8 °C and use within 24 hours. Any unused
infusion solution should be discarded 24 hours after it was prepared.
Medicines should not be disposed of via wastewater or household waste. Your doctor or nurse will
dispose of any medicine that is no longer required. These measures will help to protect the
environment.
43
6.
FURTHER INFORMATION
What Arzerra contains
-
The other ingredients are arginine, sodium acetate (E262), sodium chloride, polysorbate 80
(E433), edetate disodium (E386), hydrochloric acid (E507) (for pH-adjustment), water for
injections..
What Arzerra looks like and contents of the pack
Arzerra is a colourless concentrate for solution for infusion.
Arzerra 100 mg
is available in a pack containing 3 vials and two extension sets. Each glass vial is
closed with a latex-free rubber stopper and aluminium over-seal, and contains 5 ml of concentrate
(100 mg of ofatumumab).
Arzerra 1,000 mg
is available in a pack containing 1 vial and two extension sets. Each glass vial is
closed with a latex-free rubber stopper and aluminium over-seal, and contains 50 ml of concentrate
(1,000 mg of ofatumumab).
Marketing Authorisation Holder
Glaxo Group Ltd, Glaxo Wellcome House, Berkeley Avenue, Greenford, Middlesex, UB6 0NN,
United Kingdom.
Manufacturer
Glaxo Operations UK Limited (Trading as Glaxo Wellcome Operations), Harmire Road, Barnard
Castle, County Durham, DL12 8DT, United Kingdom.
44
-
The active substance is ofatumumab. One ml of concentrate contains 20 mg of ofatumumab.
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
België/Belgique/Belgien
GlaxoSmithKline s.a./n.v.
Tél/Tel: + 32 (0)2 656 21 11
Luxembourg/Luxemburg
GlaxoSmithKline s.a./n.v.
Belgique/Belgien
Tél/Tel: + 32 (0)2 656 21 11
България
ГлаксоСмитКлайн ЕООД
Teл.: + 359 2 953 10 34
Magyarország
GlaxoSmithKline Kft.
Tel.: + 36 1 225 5300
Česká republika
GlaxoSmithKline s.r.o.
Tel: + 420 222 001 111
gsk.czmail@gsk.com
Malta
GlaxoSmithKline Malta
Tel: + 356 21 238131
Danmark
GlaxoSmithKline Pharma A/S
Tlf: + 45 36 35 91 00
dk-info@gsk.com
Nederland
GlaxoSmithKline BV
Tel: + 31 (0)30 6938100
nlinfo@gsk.com
Deutschland
GlaxoSmithKline GmbH & Co. KG
Tel.: + 49 (0)89 36044 8701
produkt.info@gsk.com
Norge
GlaxoSmithKline AS
Tlf: + 47 22 70 20 00
firmapost@gsk.no
Eesti
GlaxoSmithKline Eesti OÜ
Tel: + 372 6676 900
estonia@gsk.com
Österreich
GlaxoSmithKline Pharma GmbH
Tel: + 43 (0)1 97075 0
at.info@gsk.com
Ελλάδα
GlaxoSmithKline A.E.B.E.
Τηλ: + 30 210 68 82 100
Polska
GSK Commercial Sp. z o.o.
Tel.: + 48 (0)22 576 9000
España
GlaxoSmithKline, S.A.
Tel: + 34 902 202 700
es-ci@gsk.com
Portugal
GlaxoSmithKline – Produtos Farmacêuticos, Lda.
Tel: + 351 21 412 95 00
FI.PT@gsk.com
France
Laboratoire GlaxoSmithKline
Tél.: + 33 (0)1 39 17 84 44
diam@gsk.com
România
GlaxoSmithKline (GSK) S.R.L.
Tel: + 4021 3028 208
Ireland
GlaxoSmithKline (Ireland) Limited
Tel: + 353 (0)1 4955000
Slovenija
GlaxoSmithKline d.o.o.
Tel: + 386 (0)1 280 25 00
medical.x.si@gsk.com
Ísland
GlaxoSmithKline ehf.
Sími: + 354 530 3700
Slovenská republika
GlaxoSmithKline Slovakia s. r. o.
Tel: + 421 (0)2 48 26 11 11
recepcia.sk@gsk.com
45
Italia
GlaxoSmithKline S.p.A.
Tel: + 39 (0)45 9218 111
Suomi/Finland
GlaxoSmithKline Oy
Puh/Tel: + 358 (0)10 30 30 30
Finland.tuoteinfo@gsk.com
Κύπρος
GlaxoSmithKline (Cyprus) Ltd
Τηλ: + 357 22 39 70 00
Sverige
GlaxoSmithKline AB
Tel: + 46 (0)8 638 93 00
info.produkt@gsk.com
Latvija
GlaxoSmithKline Latvia SIA
Tel: + 371 67312687
lv-epasts@gsk.com
United Kingdom
GlaxoSmithKline UK
Tel: + 44 (0)800 221441
customercontactuk@gsk.com
Lietuva
GlaxoSmithKline Lietuva UAB
Tel: + 370 5 264 90 00
info.lt@gsk.com
This leaflet was last approved in
{MM/YYYY}.
This medicine has been given “conditional approval”.
This means that there is more evidence to come about this medicine. The European Medicines Agency
(EMA) will review new information on the medicine every year and this leaflet will be updated as
necessary.
Detailed information on this medicine is available on the European Medicines Agency (EMA) web
site:
http://www.ema.europa.eu
/.
46
-------------------------------------------------------------------------------------------------------------------------
The following information is intended for medical or healthcare professionals only:
1) 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.
2) How to dilute the solution for infusion
The Arzerra concentrate must be diluted in sodium chloride 9 mg/ml (0.9%) solution for
injection prior to administration, using aseptic technique.
300 mg dose
- Use 3 x 100 mg/5 ml vials (15 ml total, 5 ml per vial):
•
withdraw and discard 15 ml from a 1,000 ml bag of sodium chloride 9 mg/ml (0.9%) solution for
injection
•
withdraw 5 ml of ofatumumab from each of 3 x 100 mg vials and inject into the 1,000 ml bag
•
do not shake
, mix diluted solution
by
gentle inversion.
2,000 mg dose
– Use 2 x 1,000 mg/50 ml 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 x 1,000 mg vials and inject into the 1,000 ml bag
•
do not shake
, mix diluted solution
by gentle inversion.
3)
How to administer the diluted solution
Arzerra must not be administered as an intravenous push or bolus.
Administer using an
intravenous infusion pump, 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 of the SmPC), through a
peripheral line or indwelling catheter, according to the schedule below:
Infusions 1 and 2: schedule
Time (minutes)
ml/hour
0 – 30
12
31 – 60
25
61 – 90
50
91 – 120
100
121 +
200
47
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 of the SmPC), through a
peripheral line or indwelling catheter, according to the schedule below:
Infusions 3 to 12: schedule
Time (minutes)
ml/hour
0 – 30
25
31 – 60
50
61 – 90
100
91 – 120
200
121 +
400
If any adverse reactions are observed,
infusion rates should be reduced, according to section 4.2 of
the Summary of Product Characteristics.
Any unused product or waste material should be disposed of in accordance with local requirements.
48
Source: European Medicines Agency
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