Download Product specifications for DC Bead LUMI™ DC Bead LUMI

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DC Bead LUMI™ Radiopaque Embolic
Drug-Eluting Bead
INSTRUCTIONS FOR USE
STERILE:SINGLE USE ONLY:
(Do not use if package is opened or damaged)
DESCRIPTION:
DC Bead LUMI™ are precisely calibrated, radiopaque, biocompatible,
non-resorbable hydrogel beads. The beads are produced from polyvinyl
alcohol and contain a covalently bound radiopaque moiety. The beads are
capable of loading and eluting doxorubicin or irinotecan.
DC Bead LUMI™ is manufactured to be inherently radiopaque and visible
under imaging (Computed Tomography [CT], Cone Beam Computed
Tomography [CBCT] and Fluoroscopy). DC Bead LUMI™ is available in two
size ranges:
Table 1: Product specifications
for DC Bead LUMI™
Label Color
Size
Black
70-150µm
Yellow
100-300µm
PRESENTATION:
• 10ml glass vial
• Each vial contains approximately 2ml of product in sterile phosphate
buffered saline. The total volume of DC Bead LUMI™ and sterile
physiological saline is approximately 8ml.
• The vial is stopper sealed by an aluminium cap with a colour-coded lid.
• Each package contains a 20mm ViaLok™ Vented Vial Access Device
(Yukon Medical LLC, 4021 Stirrup Creek, Durham, NC USA, CE0086) for
removal of DC Bead LUMI™ from the vial.
• DC Bead LUMI™ is intended for single patient use only. Do not
re-sterilise. Discard any unused material.
STORAGE:
• Unopened DC Bead LUMI™ should be stored in a dry place in its
original packaging. Protect the product from light.
• Use by the date indicated on the vial label.
• Do not refrigerate or freeze.
• Storage and handling of doxorubicin or irinotecan should be in
accordance with the respective manufacturer’s instructions.
Storage of doxorubicin-loaded DC Bead LUMI™
• Doxorubicin-loaded DC Bead LUMI™ can be stored in pure contrast
agent protected from light for 7 days in a refrigerator at 2-8ºC or for
4 hours at ambient temperature (not exceeding 25ºC) assuming that
an aseptic loading process has been completed.
Storage of irinotecan-loaded DC Bead LUMI™
• Once mixed with contrast media, DC Bead LUMI™ loaded with
irinotecan must be used immediately.
Page 1 of 22
INDICATIONS:
DC Bead LUMI™ can be used as an embolic agent with or without delivery
of doxorubicin or irinotecan.
Unloaded DC Bead LUMI™ is intended to be used for the embolisation of
non-malignant hypervascular tumors and arteriovenous malformations (AVMs).
For the use in malignant indications:
• DC Bead LUMI™ is primarily intended as an embolic agent for the
local treatment of malignant hypervascularised tumour(s) in the liver.
• DC Bead LUMI™ is compatible with doxorubicin for the local
treatment of tumours in patients with hepatocellular carcinoma (HCC).
Doxorubicin can be loaded prior to embolisation and then as a
secondary action, the beads will elute a local, controlled and sustained
dose to the tumour after embolisation.
• DC Bead LUMI™ is also intended to embolise the vessels supplying
malignant colorectal cancer metastasised to the liver (mCRC).
• DC Bead LUMI™ is compatible with irinotecan which can be loaded
prior to embolisation and then as a secondary action, the beads will
elute a local, controlled and sustained dose to the liver metastases
from colorectal cancer after embolisation.
WARNINGS:
• The use of doxorubicin or irinotecan-loaded DC Bead LUMI™
represents an unlicensed method of administration of these medicinal
products.
• It is the doctor’s responsibility to give due consideration to the details
in the drug product marketing authorisation in deciding which drug
(either doxorubicin or irinotecan) to load DC Bead LUMI™ with and
whether loading with that drug is appropriate for the patient under
his/her care. The relevant Summary of Product Characteristics (SmPC)
must be consulted. The type and dose of drug should also be assessed
according to the individual patient’s clinical circumstances.
• Extravasation and Tissue Necrosis: Extravasation of doxorubicin can
result in severe local tissue injury and necrosis requiring wide excision
and skin grafting. If signs or symptoms of skin extravasation occur with
doxorubicin-loaded DC Bead LUMI™, immediately terminate the
procedure. If appropriate, administer dexrazoxane at the site of
extravasation as soon as possible and within the first 6 hours after
extravasation.
• Systemic exposure to doxorubicin or irinotecan can occur. Related side
effects that might occur are listed below in section “Drug-specific
undesirable effects”.
• Due to the known cytotoxic, mutagenic and embryotoxic properties of
doxorubicin and embryotoxic / teratogenic properties of irinotecan,
drug-loaded DC Bead LUMI™ should not be used during pregnancy
unless clearly necessary, women should not breastfeed and women /
men of childbearing potential should use adequate contraceptive
measures as outlined in the relevant Summary of Product
Characteristics (SmPC).
Page 2 of 22
CONTRAINDICATIONS:
Use of DC Bead LUMI™ loaded with chemotherapeutic agents is
contraindicated in the following situations:
• Paediatric patients.
• Patients with Child-Pugh Class B (≥8) and Class C cirrhosis or a
bilirubin level > 3.0 mg/dl.
• Patients with renal dysfunction as evidenced by a serum creatine
>2.0mg/dl.
Use of DC Bead LUMI™ (unloaded or loaded with chemotherapeutic
agents) is contraindicated in the following situations:
• Patients intolerant to vascular occlusion procedures.
• Vascular anatomy that precludes catheter placement or injection of
embolics.
• Presence or likely onset of vasospasm.
• Presence or likely onset of haemorrhage.
• Presence of severe atheromatous disease.
• Presence of feeding arteries smaller than any distal branch from which
they emerge.
• Presence of patent extra-to-intracranial anastomoses or shunts.
• Presence of collateral vessel pathways potentially endangering normal
territories during the embolisation.
• Presence of end arteries leading directly to cranial nerves.
• Presence of arteries supplying the lesion not large enough to accept
DC Bead LUMI™.
• Embolisation of non-malignant tumours when loaded with
chemotherapeutic drug.
• Presence of high-flow arteriovenous shunt with a diameter greater
than the selected bead size that cannot be coiled or blocked.
• Embolisation of AV shunts (i.e. where the blood does not pass through
the arterial/capillary/venous transition but directly from artery to vein.
• Any vasculature where DC Bead LUMI™ could pass directly into the
internal carotid artery or other non-target territories.
• The use of Visipaque (Iodixanol) with irinotecan-loaded DC Bead LUMI™.
• Any neurovascular or central circulatory system indication.
• Vascular resistance peripheral to the feeding arteries precluding passage
of DC Bead LUMI™ into the lesion/tumour.
• Prior biliary surgery, bile duct dilatation or biliary sphincterotomy.
• Do not use in the pulmonary arterial vasculature.
Contraindications when using doxorubicin or irinotecan:
Refer to irinotecan or doxorubicin packaging insert (SmPC) for
contraindications regarding use.
Page 3 of 22
CAUTIONS:
• Do not use if the vial or packaging appears damaged.
• Select the size and quantity of DC Bead LUMI™ appropriate for
pathology to be treated. Embolisation with DC Bead LUMI™ should only
be performed by physicians who have received appropriate
interventional occlusion training in the region intended to be embolised.
• Chemotherapy-loaded DC Bead LUMI™ should only be prescribed,
prepared and administered by professionals who have been trained in
the appropriate use of cytotoxic drugs.
• Please refer to section 6.6 “Special precautions for disposal and other
handling” of the SmPC for the corresponding drug for information
regarding special precautions on the disposal and other handling of
cytotoxic agents.
• Use only the recommended non-ionic contrast agents (see table 6). Refer
to the SmPC of the selected contrast agent prior to administration to a
patient regarding warnings, potential complications, contraindications
and precautions of the contrast agent.
• Consider upsizing DC Bead LUMI™ in the presence of AV shunts if
angiographic evidence of embolisation does not appear quickly during
delivery.
• Consideration should be given to Tc99m-MAA scanning if there is
suspicion of AV shunting.
• Sterile and single-use product. Do not reuse due to risk of infection.
• If there are any symptoms of unwanted embolisation during injection,
consider stopping the procedure to evaluate the possibility of shunting.
Such symptoms may include changes in patient’s vital signs, such as
hypoxia or central nervous system changes.
• In case of hypersensitivity to contrast agents it is recommended not to
use DC Bead LUMI™.
• Non-target embolisation may occur in the presence of arteriovenous
anastomosis, branch vessels which lead away from the targeted
embolisation area, or emergent vessels not evident prior to
embolisation. The patient may experience severe complications as a
result of non target embolisation. Special care should be taken to avoid
ischaemia of non-tolerant, non-targeted tissue.
• Consider risks of radiation from angiography and fluoroscopy used to
visualise the blood vessels during embolisation which may include a
radiation burn and risks to future fertility.
• Do not exceed a max. number of two vials per treatment session.
Page 4 of 22
Cautions associated with doxorubicin-loaded DC Bead LUMI™
• Based on evidence from the literature for the equivalent product,
DC Bead™, a recommended dose of 37.5mg doxorubicin per 1ml of
DC Bead LUMI™ should not be exceeded. Exceeding the maximum
recommended dose may lead to significant systemic exposure to
doxorubicin and related side effects. Up to 4ml doxorubicin loaded
DC Bead LUMI™ (total 150 mg) may be used per treatment session.
(Lencioni R et al, 2012 for DC Bead™). Systemic exposure to doxorubicin
can also occur with this standard dosage of DC Bead LUMI™. However,
pharmacokinetic data of the equivalent product, DC Bead™, have shown
that systemic exposure levels are significantly reduced compared to
conventional transarterial chemoembolisation and intravenous
administration (AUC of approximately 520 hours.ng/ml for DC Bead™ vs
approximately 1530 hours.ng/ml for conventional TACE and 3890
hours.ng/ml for intravenous doxorubicin).
• Evidence from the literature for the equivalent product, DC Bead™,
indicates that patients receive between 1 and 5 treatments with
DC Bead™ loaded with doxorubicin (up to 150mg/treatment), depending
on their clinical and radiologic response. The duration of time between
procedures should be between 1 and 2 months with possibly shorter
intervals for bilobar disease (see below under “treatment / retreatment”).
• DC Bead LUMI™ beads do not change in size after drug loading.
• Doxorubicin is sensitive to light. Storage of doxorubicin loaded product
should be protected from light (see “Storage”).
Page 5 of 22
Cautions associated with irinotecan-loaded DC Bead LUMI™
• Based on evidence from the literature for the equivalent product,
DC Bead™, a recommended dose of 50mg irinotecan per 1ml of
DC Bead LUMI™ should not be exceeded. Exceeding the maximum
recommended dose may lead to significant systemic exposure to
irinotecan and related side effects. Up to 2ml irinotecan-loaded
DC Bead LUMI™ (total 100mg) may be used per treatment session
(Lencioni R et al, 2014 for DC Bead™). Systemic exposure to irinotecan
can also occur with this standard dosage of DC Bead LUMI™. However,
pharmacokinetic data of the equivalent product, DC Bead™, have shown
that systemic exposure levels are significantly reduced compared to
intravenous administration (AUC of approximately 1680 hours.ng/ml for
DC Bead™ vs 10,200 hours.ng/ml for intravenous irinotecan). Systemic
exposure to SN-38 for the equivalent product DC Bead™ (AUC
approximately 280 hours.ng/ml), is within the expected AUC range for IV
irinotecan treatment of colorectal cancer.
• Evidence from the literature for the equivalent product, DC Bead™,
indicates that most patients with liver metastases from colorectal cancer
receive up to 2 treatments with the equivalent product, DC Bead™,
loaded with irinotecan (up to 100mg per treatment), depending on their
clinical and radiologic response. The duration of time between procedures
should be between 3 - 4 weeks with possibly shorter intervals for bilobar
disease (see below under “treatment / retreatment”).
• DC Bead LUMI™ beads do not change in size after drug loading.
• It is not recommended that saline solution be added to the
irinotecan-loaded DC Bead LUMI™ as this will release irinotecan into the
delivery solution potentially leading to systemic delivery of drug.
• DC Bead LUMI™ mixed with contrast agent should be administered
immediately after preparation.
• Based on experience with the equivalent product DC Bead™, patients
with metastases from colorectal cancer treated with irinotecan-loaded
DC Bead LUMI™ may experience more immediate side effects for
example, fever, abdominal pain and vomiting, compared with patients
who had received an irinotecan-based systemic regimen. Patients treated
with systemic chemotherapy however, have a much higher incidence of
systemic drug effects such as diarrhoea, asthenia, leukopenia and anaemia
(Fiorentini et al, 2012 for DC Bead™).
Page 6 of 22
SPECIAL POPULATIONS
The following section describes the available clinical data of the equivalent
product DC Bead™ and conclusions thereof regarding the use of
DC Bead LUMI™, when loaded with doxorubicin to treat certain subgroups of
patients with HCC or irinotecan to treat certain subgroups of patients with
liver metastases from colorectal cancer.
Doxorubicin-loaded DC Bead LUMI™
Elderly Patients
In clinical practice, no upper age limit is established for use of
chemoembolisation procedures whenever patient characteristics and
baseline laboratory tests are within those established for such procedures.
An analysis of treatment-related adverse events by age group (<65 years of
age vs. ≥65 years of age) for those patients treated with doxorubicin-loaded
DC Bead™ in the company sponsored studies, showed no difference in terms
of incidence 86.7% vs. 84.4% for such events. No difference was found either
for treatment-related serious adverse events (25% vs. 21.9%). Based on the
above information, use of chemotherapy-loaded DC Bead LUMI™ is allowed
in elderly patients.
Patients with Child-Pugh A and B Cirrhosis
Biocompatibles UK Ltd sponsored the PRECISION V study which included
patients with Child-Pugh A and B cirrhosis. Of those patients included in the
DC Bead™ treatment arm, 77 had Child-Pugh A cirrhosis and 16 had
Child-Pugh B cirrhosis. Although more patients in the DC Bead™ group with
Child-Pugh B cirrhosis, compared with Child-Pugh A cirrhosis, had Serious
Adverse Events (SAEs) (8/16 patients, or 50.0% vs. 25/77 patients, or 32.5%),
the reverse was observed for patients with SAEs occurring within 30 days of
the treatment procedure (3/16, or 18.8%, of Child-Pugh B patients, compared
with 19/77, or 24.7%, of Child-Pugh A patients). In patients randomised to
cTACE, the incidence of SAEs was similar in the Child-Pugh A and B groups
(36.8% and 33.7%, respectively). However, the relatively low number of
patients with Child-Pugh B cirrhosis limits the interpretation of these findings.
Extensive data are available in the literature supporting the safety and
efficacy of DC Bead™ with doxorubicin in the treatment of HCC patients with
Child-Pugh A (>500 patients) or Child-Pugh B (>300 patients) cirrhosis
(Prajapati et al. 2013; Boatta et al. 2013; Vadot et al. 2015; Nasser et al.
2014; Kalva et al. 2014; Xing et al. 2015).
Based on the existing evidence, use of doxorubicin-loaded DC Bead LUMI™
is allowed in HCC patients with Child-Pugh A or B (< 8) cirrhosis.
Page 7 of 22
Patients with Renal Impairment
Serum creatinine >2.0 mg/dl constitutes an absolute contraindication for
TACE procedures (Liapi & Geschwind 2011). Patients were excluded from the
company sponsored studies if they had renal insufficiency/failure or serum
creatinine was higher than 2 mg/dl.
Patients in whom only limited or no data are available on DC Bead™ with
doxorubicin
In the following patient groups, there are limited or no data available on
DC Bead™ with doxorubicin:
Patients who have received previous systemic chemotherapy
Patients who have received previous radiotherapy
Patients with advanced liver disease
Patients with advanced tumoural disease, including diffuse HCC
Irinotecan-loaded DC Bead LUMI™
Elderly Patients
In clinical practice, no upper age limit is established for use of
chemoembolisation procedures whenever patient’s characteristics and
baseline laboratory tests are within those established for such procedures.
Recent publications on the use of irinotecan-loaded DC Bead™ in patients
with liver metastases from colorectal cancer included patients with mean
age of around 64 years of age (range 44-85 years) (Eichler et al. 2012,
Fiorentini et al. 2012, Martin et al. 2012).
Based on the above information, use of chemotherapy-loaded
DC Bead LUMI™ is allowed in elderly patients.
Patients with Renal Impairment
Serum creatinine >2.0 mg/dl constitutes an absolute contraindication for
TACE procedures (Liapi & Geschwind, CVIR 2010). Patients were excluded
from the company-sponsored studies if they had renal insufficiency/failure or
serum creatinine was higher than 2mg/dl.
Page 8 of 22
POTENTIAL COMPLICATIONS:
• Undesirable reflux or passage of DC Bead LUMI™ into normal arteries
adjacent to the targeted lesion or through the lesion into other arteries
or arterial beds.
• Non-target embolisation, for example:
- Gastroduodenal ulcerations
- Pulmonary embolisation
- Pancreatitis, cholecystitis
• Liver insufficiency, dysfunction or decompensation (a known
complication of chemoembolisation, but may also result from
progression of underlying disease)
• Deep vein thrombosis, or clotting of a deep vein in patient’s leg(s)
• Liver vein thrombosis
• Thrombosis of the artery at the incision site for arterial access
• Ischaemia at an undesirable location.
• Capillary bed saturation and tissue damage.
• Ischaemic stroke or ischaemic infarction.
• Vessel or lesion rupture and haemorrhage.
• Neurological deficits including cranial nerve palsies.
• Vasospasm.
• Recanalisation.
• Foreign body reactions necessitating medical intervention.
• Infection necessitating medical intervention.
• Clot formation at the tip of the catheter and subsequent dislodgement
causing arterial thromboembolic sequelae.
• Post-embolisation syndrome (which may include nausea, fever, pain)and
increases in laboratory parameters such as elevated liver enzymes.
• Liver abscess
• Death.
• Allergic reactions to contrast agents or DC Bead LUMI™ in patients who
are allergic or with known sensitivity to iodine / iodine containing
substances.
• Embolisation of the wrong artery or migration of the microspheres to
other parts of the body, which may necessitate further treatment.
• Haematoma, or bruising, or arterial aneurysm at the arterial access
incision site.
The frequencies of these complications have not yet been determined due to
the lack of clinical experience with DC Bead LUMI™
Page 9 of 22
DRUG-SPECIFIC UNDESIRABLE EFFECTS
DC Bead™ and DC Bead LUMI™ have been developed in order to offer
localised drug delivery to liver tumours with corresponding reduced systemic
toxicity. Pharmacokinetic profiles and patient tolerability benefits have been
demonstrated in studies with both doxorubicin- and irinotecan-loaded
DC Bead™ (Varela et al. 2007, Eichler et al. 2012, Lammer et al. 2010 and
Fiorentini et al. 2012). Table 2 shows the undesirable effects listed within
the product labelling for doxorubicin.
Table 2: Undesirable Effects Listed Within the Product Labelling for Doxorubicin
System Organ Class
Undesirable Effects
Neoplasms Benign and
Malignant (including cysts
and polyps)
The occurrence of secondary acute myeloid
leukaemia with or without a pre-leukaemic
phase has been reported rarely in patients
concurrently treated with doxorubicin in
association with DNA-damaging
antineoplastic agents. Such cases could have
a short (1-3 year) latency period. Acute
lymphocytic leukaemia and acute
myelogenous leukaemia.
Blood and Lymphatic
System Disorders
Haematological monitoring should be
undertaken regularly in both haematological
and non haematological conditions, because
of the possibility of bone-marrow depression
which may become evident around ten days
from the time of administration. Clinical
consequences of doxorubicin bone
marrow/haematological toxicity may be
fever, infections, sepsis/septicaemia, septic
shock, haemorrhages, tissue hypoxia or
death. Leucopenia, neutropenia, anaemia and
thrombocytopenia.
Immune System Disorders
Anaphylaxis
Metabolism and Nutrition
Disorders
Anorexia, dehydration and hyperuricaemia.
Eye Disorders
Conjunctivitis / keratitis and lacrimation.
Page 10 of 22
System Organ Class
Undesirable Effects
Cardiac Disorders
Cardiotoxicity may be manifested in
tachycardia including supraventricular
tachycardia and ECG changes. Routine ECG
monitoring is recommended and caution
should be exercised in patients with
impaired cardiac function. Severe cardiac
failure may occur suddenly without
premonitory ECG changes. Tachyarrhythmias,
atrio-ventricular and bundle branch block,
asymptomatic reduction in left ventricular
ejection fraction and congestive heart failure.
Vascular Disorders
Phlebitis, thrombophlebitis,
thromboembolism, hot flushes and shock.
Gastrointestinal Disorders
Nausea, vomiting and mucositis/stomatitis,
hyperpigmentation of oral mucosa,
oesophagitis, abdominal pain, gastric
erosions, gastrointestinal tract bleeding,
diarrhoea and colitis.
Hepatobiliary Disorders
Changes in transaminase levels.
Skin and Subcutaneous
Tissue Disorders
Alopecia occurs frequently, including the
interruption of beard growth, but all hair
growth normally resumes after treatment is
stopped. Skin rashes/itch, local toxicity, skin
changes, skin and nail hyperpigmentation,
photosensitivity, hypersensitivity to
irradiated skin ('radiation recall reaction'),
urticaria, acral erythema and plantar-palmar
dysaesthesia.
Renal and Urological
Disorders
Doxorubicin may impart a red colour to urine
particularly to the first specimen passed after
the injection and patients should be advised
that this is no cause for alarm.
Reproductive System and
Breast Disorders
Amenorrhoea, oligospermia and
azoospermia.
General Disorders and
Administration Site
Conditions
The risk of thrombophlebitis at the injection
site may be minimised by following the
procedure for administration recommended
above. A stinging or burning sensation at the
site of administration signifies a small
degree of extravasation and the infusion
should be stopped and re-started in another
vein. Fever, malaise, asthenia and chills.
Investigations
ECG abnormalities
Table 3 shows the undesirable effects listed within the product labelling for
Irinotecan.
Page 11 of 22
Table 3: Undesirable Effects Listed Within the
Product Labelling for Irinotecan
System Organ Class
Undesirable Effects
Gastrointestinal disorder
Delayed diarrhoea
Diarrhoea (occurring more than 24 hours
after administration) is a dose-limiting
toxicity.
In monotherapy: Severe diarrhoea was
observed in 20 % of patients who follow
recommendations for the management of
diarrhoea. Of the evaluable cycles, 14 % have
a severe diarrhoea. The median time of onset
of the first liquid stool was on day 5 after the
infusion.
In combination therapy: Severe diarrhoea
was observed in 13.1 % of patients who
follow recommendations for the
management of diarrhoea. Of the evaluable
cycles, 3.9 % have a severe diarrhoea.
Uncommon cases of pseudo-membranous
colitis have been reported, one of which has
been documented bacteriologically
(Clostridium difficile).
Nausea and vomiting
In monotherapy : Nausea and vomiting were
severe in approximately 10% of patients
treated with antiemetics.
In combination therapy : A lower incidence of
severe nausea and vomiting was observed
(2.1% and 2.8% of patients respectively).
Dehydration
Episodes of dehydration commonly
associated with diarrhoea and/or vomiting
have been reported. Infrequent cases of renal
insufficiency, hypotension or
cardio-circulatory failure have been observed
in patients who experienced episodes of
dehydration associated with diarrhoea and/or
vomiting.
Other gastrointestinal disorders
Constipation has been observed :
• in monotherapy : in less than 10% of
patients (monotherapy)
• in combination therapy : 3.4% of patients.
Infrequent cases of intestinal obstruction,
ileus, or gastrointestinal haemorrhage and
rare cases of colitis, including typhlitis,
ischemic and ulcerative colitis, were
reported. Rare cases of intestinal perforation
were reported. Other mild effects include
anorexia, abdominal pain and mucositis. Rare
cases of symptomatic or asymptomatic
pancreatitis have been associated with
irinotecan therapy.
Page 12 of 22
Blood disorders
Neutropenia is a dose-limiting toxic effect.
Neutropenia was reversible and not
cumulative; the median day to nadir was 8
days whatever the use in monotherapy or in
combination therapy.
In monotherapy : Neutropenia was observed
in 78.7% of patients and was severe
(neutrophil count < 500 cells/mm3) in 22.6%
of patients. Of the evaluable cycles, 18 %
had a neutrophil count below 1,000
cells/mm³ including 7.6% with a neutrophil
count < 500 cells/mm³. Total recovery was
usually reached by day 22.
Fever with severe neutropenia was reported
in 6.2% of patients and in 1.7% of cycles.
Infectious episodes occurred in about 10.3%
of patients (2.5% of cycles) and were
associated with severe neutropenia in about
5.3% of patients (1.1% of cycles), and
resulted in death in 2 cases.
Anaemia was reported in about 58.7% of
patients (8% with haemoglobin < 8 g/dl and
0.9 % with haemoglobin < 6.5g/dl).
Thrombocytopenia (< 100,000 cells/mm³)
System Organ Class
Undesirable Effects
was observed in 7.4% of patients and 1.8% of
cycles with 0.9% with platelets count
≤ 50,000 cells/mm3 and 0.2% of cycles. Nearly
all the patients showed a recovery by day 22.
In combination therapy : Neutropenia was
observed in 82.5% of patients and was
severe (neutrophil count < 500 cells/mm3) in
9.8 % of patients. Of the evaluable cycles,
67.3% had a neutrophil count below 1,000
cells/mm³ including 2.7% with a neutrophil
count < 500 cells/mm³. Total recovery was
usually reached within 7-8 days.
Fever with severe neutropenia was reported
in 3.4% of patients and in 0.9% of cycles.
Infectious episodes occurred in about 2% of
patients (0.5% of cycles) and were associated
with severe neutropenia in about 2.1% of
patients (0.5% of cycles), and resulted in
death in 1 case.
Anaemia was reported in 97.2% of patients
(2.1% with haemoglobin < 8 g/dl).
Thrombocytopenia (< 100,000 cells/mm³)
was observed in 32.6% of patients and 21.8%
of cycles. No severe thrombocytopenia
(≤ 50,000 cells/mm³) has been observed.
One case of peripheral thrombocytopenia
with antiplatelet antibodies has been
reported in the post-marketing experience.
Page 13 of 22
Infection and infestation
Infrequent cases of renal insufficiency,
hypotension or cardio-circulatory failure
have been observed in patients who
experienced sepsis.
General disorders and
infusion site reactions
Acute cholinergic syndrome
Severe transient acute cholinergic syndrome
was observed in 9 % of patients treated in
monotherapy. The main symptoms were
defined as early diarrhoea and various other
symptoms such as abdominal pain,
conjunctivitis, rhinitis, hypotension,
vasodilatation, sweating, chills, malaise,
dizziness, visual disturbances, myosis,
lacrimation and increased salivation
occurring during or within the first 24 hours
after the infusion. These symptoms disappear
after atropine administration (see « Special
warnings and precautions for use » from
SmPC of the corresponding drug).
Asthenia was severe in less than 10 % of
patients treated in monotherapy and in 6.2 %
of patients treated in combination therapy.
The causal relationship to irinotecan
treatment has not been clearly established.
Fever in the absence of infection and without
concomitant severe neutropenia, occurred in
12 % of patients treated in monotherapy and
in 6.2 % of patients treated in combination
therapy.
Mild infusion site reactions have been
reported although uncommonly.
Cardiac disorder
Rare cases of hypertension during or
following the infusion have been reported.
Respiratory disorders
Interstitial pulmonary disease presenting as
pulmonary infiltrates is uncommon during
irinotecan therapy. Early effects such as
dyspnoea have been reported.
Skin and subcutaneous
tissue disorders
Alopecia was very common and reversible.
Mild cutaneous reactions have been reported
although uncommonly.
Immune system disorders
Uncommon mild allergy reactions and rare
cases of anaphylactic/anaphylactoid
reactions have been reported.
Musculoskeletal
disorders
Early effects such as muscular contraction or
cramps and paresthesia have been reported.
Page 14 of 22
Laboratory tests:
In monotherapy: Transient and mild to
moderate increases in serum levels of either
transaminases, alkaline phosphatase or
bilirubin were observed in 9.2%, 8.1% and
1.8% of the patients, respectively, in the
absence of progressive liver metastasis.
Transient and mild to moderate increases of
serum levels of creatinine have been
observed in 7.3% of the patients.
In combination therapy: transient serum
levels (grades 1 and 2) of either SGPT, SGOT,
alkaline phosphatase or bilirubin were
observed in 15%, 11%, 11% and 10% of the
patients, respectively, in the absence of
progressive liver metastasis. Transient grade
3 were observed in 0%, 0%, 0% and 1% of
the patients, respectively. No grade 4 was
observed.
Increases of amylase and/or lipase have been
very rarely reported.
Rare cases of hypokalemia and hyponatremia
mostly related with diarrhea and vomiting
have been reported.
Nervous system disorders
There have been very rare postmarketing
reports of transient speech disorders
associated with irinotecan infusions.
Vascular disorders
Irinotecan has been rarely associated with
thromboembolic events (pulmonary
embolism, venous thrombosis, and arterial
thromboembolism) in patients presenting
with multiple risk factors in addition to the
underlying neoplasm
CHOICE OF BEAD SIZE:
Care should be taken to choose the appropriate size range of
DC Bead LUMI™ that best matches the pathology (i.e. vascular target/vessel
size / AVM nidus). Either 100–300µm or 70-150µm
DC Bead LUMI™ are recommended for standard HCC procedures or for the
treatment of liver metastases from colorectal cancer. The choice of smaller
bead size is based on the demonstration in the equivalent product
DC Bead™, that such particles are delivered inside the tumour or in close
proximity to the tumour margin and thus are suitable for drug delivery and
precise embolisation. However, individual patient and tumour characteristics,
particularly the identification of arteriovenous shunting, should be taken into
account when the safety of the treatment and the choice of DC Bead LUMI™
size are determined. In the case of significant arterioportal or hepatic venous
shunting, embolisation of the shunt with gelfoam pledgets is recommended
before proceeding with administration of DC Bead LUMI™. Angiographic
confirmation that the shunt is no longer present must be obtained before
DC Bead LUMI™ injection can be performed, and a larger bead size using an
equivalent bead product may be preferred.
Page 15 of 22
TREATMENT AND RETREATMENT:
HCC treatment with doxorubicin-loaded DC Bead LUMI™:
In patients with residual viable tumour—including partial response, stable
disease, and progressive disease according to mRECIST—further treatment
with DC Bead LUMI™ (max. of 5 treatments, up to 150mg doxorubicin /
treatment) can be scheduled after 4–8 weeks in the absence of contraindications based on experience with the equivalent product DC Bead™.
Obtaining confirmation that the liver enzymes have returned to baseline
before repeating treatment is recommended.
In bilobar tumours, the two hepatic lobes can be treated in separate
treatment sessions 2–4 weeks apart, in the absence of complications
requiring a longer time interval between the two sessions based on experience with the equivalent product DC Bead™.
Obtaining confirmation that the liver enzymes have returned to baseline
before performing the second treatment session is recommended.
mCRC treatment with irinotecan-loaded DC Bead LUMI™:
In the case of unilobar disease, up to two lobar treatments can be scheduled,
each with up to 100mg irinotecan per treatment, separated by 3–4 weeks in
the absence of contraindications based on experience with the equivalent
product DC Bead™.
Obtaining confirmation that the liver enzymes have returned to baseline
levels before performing the second treatment is recommended.
For bilobar disease, four lobar treatments should be planned, each with up to
100mg irinotecan-loaded in one DC Bead LUMI™ vial, every 2 weeks in the
absence of complications requiring a longer time interval between the two
sessions based on experience with the equivalent product DC Bead™.
Obtaining confirmation that the liver enzymes have returned to baseline
levels before performing each subsequent treatment is recommended.
LOADING AND ADMINISTRATION OF DC BEAD LUMI™
• Once opened, DC Bead LUMI™ should be used within 4 hours if they are
kept at room temperature or within 24 hours if they are stored in a
refrigerator at 2-8°C, as the preparation and loading conditions of
DC Bead LUMI™ are performed outside of the manufacturer’s control, i.e.
storage once the vial has been pierced is under the responsibility of the
user.
• Carefully evaluate the vascular network associated with the site to be
embolised using high-resolution imaging prior to beginning the
embolisation procedure. Care should be taken to choose the appropriate
size range of DC Bead LUMI™ that best matches the pathology (i.e.
vascular target/vessel size / AVM nidus)
• When removing the vial from outer packaging, visually inspect for
breakage or sharp edges prior to use.
• Use appropriate protective clothing and hygiene measures.
• Choose a delivery catheter based on the size of the target vessel. Use
the catheter’s minimum inner diameter measurement to determine
catheter-to-microsphere compatibility. Minimum catheter sizes are given
in table 6.
• It is recommended to monitor the embolisation procedure using X-ray
imaging techniques such as CT, CBCT and fluoroscopy.
Page 16 of 22
Notes:
• It is recommended to use non-ionic contrast agent during the delivery of
DC Bead LUMI™. Throughout the preparation, avoid the introduction of
air bubbles. If air bubbles are observed, eliminate them to prevent
potential aggregation of the microspheres.
• DC Bead LUMI™ are suitable for loading with doxorubicin or irinotecan.
• Liposomal formulations of doxorubicin are not suitable for loading into
DC Bead LUMI™
CAUTION: Due to the cytotoxicity of the chemotherapeutic agents (that may
be chosen by the prescriber for use with the device based on an informed
clinical assessment) and requirement for aseptic preparation, the procedure
is hazardous to staff and should only be undertaken by trained personnel in
appropriate, validated aseptic facilities
Preparation of DC Bead LUMI™:
1. During preparation of DC Bead LUMI™, use controlled aseptic
conditions.
2. Remove the plastic colour-coded flip cap from DC Bead LUMI™ vial but
do not remove the metal ring around the stopper. With the spike of the
ViaLok™ Vented Access Device centred to the rubber stopper of the vial,
attach the device until the retention tabs snap on the DC Bead LUMI™
vial.
Note: The ViaLok™ Vented Access Device is not for direct infusion
and should only be used for transfer of the beads into a syringe. The
access device size corresponds to vial diameter and is intended for
use with ISO-594 compatible mating Luers. DC Bead LUMI™ has only
been tested in conjunction with ViaLok™ Vented Access Device.
3. Remove and discard luer cap from the access device.
Note: To minimise risk of potential contamination, the ViaLok™
Vented Access Device protective cap shall remain attached to Luer
until accessed by the mating Luer device.
4. Attach a 10ml syringe to the luer lock of the ViaLok™ Vented Access
Device.
5. Invert vial and suspend the beads in solution by agitiating in a swirling
motion whilst drawing the DC Bead LUMI™ into the syringe.
6. Once all the solution is transferred, discontinue the agitation and
maintain the vial in the inverted position to allow the microspheres to
settle in the syringe on the plunger. Return only the clear solution to the
vial and repeat previous step to recover remaining beads from the vial.
This process may be repeated twice if required.
Note: Small traces of DC Bead LUMI™ may be retained in the vial.
7. Once DC Bead LUMI™ have settled at the bottom of the syringe,
disconnect the syringe from the ViaLok™ Vented Access Device. Expel
all packing solution to waste or suitable container, leaving only
DC Bead LUMI™ within the syringe.
Page 17 of 22
Drug loading procedure (if no drug loading is performed, proceed to “Mixing
with contrast agent”):
8. Handle the drug according to manufacturer’s guidelines. For
reconstitution of doxorubicin powder, use water for injection (WFI) to
achieve a concentration of 25mg/ml. Please use doxorubicin powder for
loading, as doxorubicin solutions have not been tested with
DC Bead LUMI™. For irinotecan loading please use irinotecan solution
(20 mg/ml).
9. Transfer the required amount of reconstituted drug into the syringe
containing DC Bead LUMI™ and agitate. Take care that the syringe is
properly sealed so as not to spill cytotoxic drug. Make sure beads are
mobilised when inverting beads during loading. Do not exceed the
recommended maximum loading dose:
•
37.5mg of doxorubicin per 1ml of DC Bead LUMI™
(equivalent to 75mg per vial).
•
50mg of irinotecan per 1ml of DC Bead LUMI™
(equivalent to 100mg per vial).
10. Follow the loading instructions as given in tables 4 and 5
Table 4: Drug loading instructions doxorubicin
Bead size
Doxorubicin Hydrochloride
70-150 µm
100 –300 µm
Loading time (min)
60 minutes
90 minutes
No of syringe inversion per
agitation step
10
10
Agitation interval during
loading (min)
5 minutes
5 minutes
Loading temperature (°C)
Room Temperature
Room Temperature
Table 5: Drug loading instructions irinotecan
Bead size
Irinotecan Hydrochloride
70-150 µm
100 –300µm
Loading time (min)
10 minutes
20 minutes
No of syringe inversion per
agitation step
10
10
Agitation interval during
loading (min)
5 minutes
5 minutes
Loading temperature (°C)
Room Temperature
Room Temperature
Page 18 of 22
11. After doxorubicin loading the solution may retain some colouration
which is to be expected and is not an indication that DC Bead LUMI™
has failed to load.
12. Expel the excess liquid into a suitable container for cytotoxic waste
following the local standard practice and the cytotoxic drug
manufacturer’s guidance, retaining a total volume of 2ml of loaded
beads. To achieve this, hold the syringe in an inverted position to let the
microspheres settle on the plunger. Ensure that microspheres are settled
prior to expelling the supernatant. Caution is required when expelling
the depleted cytotoxic solution into an appropriate container such as an
empty safety-vented bunged vial, a septum solution bag, a second
syringe via a two-way luer connector etc.).
WARNING (Doxorubicin loading): Strict adherence to the instructions,
loading times and process will ensure > 98% drug loading. The product
should not be used in the event of an intensely red opaque supernatant as
this is an indication of inadequate loading or excess of added doxorubicin.
Mixing with contrast agent:
13. DC Bead LUMI™ is now ready for use.
14. DC Bead LUMI™ should be prepared for administration using 100%
non-ionic contrast agent to obtain an optimum suspension. Please refer
to table 6 for recommended contrast agents..
15. Attach a connector to the syringe containing DC Bead LUMI™.
Using a 20ml syringe take up 20ml of contrast agent and connect to the
10ml syringe containing DC Bead LUMI™.
16. Gently mix DC Bead LUMI™ and contrast agent between syringes
through the connector, until a homogeneous suspension is achieved.
17. Remove 20ml syringe and replace with 3ml syringe for delivery. Mix
between the 10ml and 3ml syringes using a connector to obtain
homogeneous suspension of DC Bead LUMI™. After the contents of the
10ml syringe is delivered, the process can be repeated by transferring
the remaining suspension from the 20ml syringe to the 10ml syringe
through a connector.
Note: Please ensure mixing is performed between each refill of the 3ml
syringe.
Recommended Catheters and Contrast Agents:
Once prepared, DC Bead LUMI™ has been tested and shown to be
successfully delivered using the combinations of bead size, contrast medium
and microcatheters shown in Table 6.
Page 19 of 22
Table 6: Recommended catheter sizes and contrasts agents
for application with DC Bead LUMI™.
Product Size Range of
DC Bead LUMI™
Recommended
Catheter
(internal diameter)
70-150µm
(70 – 170µm)**
≥ 2.0 Fr
(0.483mm /
0.019in)
100-300µm
(70 – 340µm)**
≥ 2.4 Fr
(0.533mm /
0.021in)
Recommended Contrast
Agents
Omnipaque / Accupaque 350
(Iohexol 350)
Visipaque 320 (Iodixanol
320), for Doxorubicin
loading only*
Iomeron 400 (Iomeprol 400)
Visipaque 270 (Iodixanol
270), for Doxorubicin
loading only*
Notes:
• Other contrast agents have not been tested in conjunction with
DC Bead LUMI™.
• Isovue 300 (Solutrast 300) has been tested and is not recommended
for use due the inadequate suspension times. Contrast agents of a
similar viscosity at 20ºC should not be used with DC Bead LUMI™.
* Visipaque 270 and Visipaque 320 have been tested and are not
recommended for use with irinotecan-loaded beads as the drug is eluted
in this mixture to a significant extent.
** Potential bead size range based on manufacturers specification.
Delivery Instructions:
Note:
Please note that DC Bead LUMI™ will settle quickly in some contrast agents.
Prior to and during delivery, ensure visually that the beads are in suspension.
Please note that larger beads have shorter suspension times than the smaller
size range of DC Bead LUMI™.
1. Using standard techniques, position the delivery catheter within the
target vessel and the catheter tip as close as possible to the treatment
site to avoid inadvertent occlusion of non-target vessels.
2. Use a 3ml syringe to manage the injection pressure during catheter
delivery of the DC Bead LUMI™.
3. Slowly inject DC Bead LUMI™ solution into the delivery catheter under
under X-ray techniques such as fluoroscopy, CBCT and CT imaging while
observing the bead distribution to avoid reflux. If there is no effect on
the antegrade flow rate, choose a larger size of DC Bead LUMI™ (if
applicable) and repeat the delivery process. Exercise conservative
judgment in determining the embolisation endpoint.
4. Where necessary, saline flushes can be used to ensure full delivery of
the DC Bead LUMI™.
5. Upon completion of the treatment, remove the catheter while
maintaining gentle suction so as not to dislodge DC Bead LUMI™ that
may still be within the catheter lumen.
6. Discard any open unused DC Bead LUMI™ as well as any other ancillary
equipment used in the procedure such as the ViaLok™ Vented Access
Device, syringes, needles, catheters, etc. according to the applicable
local standard practice and the cytotoxic drug manufacturers guidelines
to dispose of cytotoxics and clinical waste.
Page 20 of 22
PACKAGE LABEL:
REF
Catalogue number
Steam Sterilized
LOT
Batch number/
Lot number
Do not reuse
Use-by date/Expiry
Protect from light/
keep away from sunlight
Protect from
moisture/keep dry
Attention see
instructions for use
8
Do not refrigerate or
freeze. DC Bead LUMI™
does not require any
special temperature
storage conditions.
Manufacturer
REFERENCES:
1. Lencioni R et al, Cardiovasc Intervent Radiol. 2012 Oct;35(5):980-5
2. Lencioni R et al, J Vasc Interv Radiol. 2014 Mar;25(3):365-9
3. Martin RCG et al, Cardiovasc Intervent Radiol. 2010 Oct;33(5):960-6
4. Marques A et al, J Vasc Interv Radiol 2013; 24:1416–1417.
5. Prajapati HJ et al, J Vasc Interv Radiol. 2013 Mar;24(3):307-15.
6. Boatta E et al, J Radiol Imaging. 2013 Apr;23(2):126-33.
7. Vadot L et al, J Clin Pharm Ther. 2015 Feb;40(1):83-90.
8. Nasser F et al, J Vasc Interv Radiol. 2014 Jul;25(7):1012-7.
9. Kalva SP et al, Cardiovasc Intervent Radiol. 2014 Apr;37(2):381-7.
10. Xing M et al, J Gastroenterol Hepatol. 2015 Jul;30(7):1167-74.
11. Liapi E and Geschwind JFH, Cardiovasc Intervent Radiol. 2011 Feb;
34(1): 37–49.
12. Eichler K et al, International Journal of Oncology Int J Oncol.
2012 Oct;41(4):1213- 20.
13. Lammer et al., Cardiovasc Intervent Radiol. 2010 Feb;33(1):41-52
14. Fiorentini G (2012) et al, AGH 2012 31(1): 39-48.
15. Martin RC 2nd et al, J Gastrointest Surg. 2012 Aug;16(8):1531-8.
16. Varela M et al., Chemoembolization of hepatocellular carcinoma with
drug eluting beads. Efficacy and doxorubicin pharmacokinetics. J.
Hepatology 2007, 46 (3): 474-481.
Page 21 of 22
Manufactured by:
Biocompatibles UK Ltd, a BTG International group company
Chapman House, Weydon Lane, Farnham, Surrey, GU9 8QL, United
Kingdom
Tel: +44 (0)1252 732 732, Fax: +44 (0)1252 732 777
http://www.btg-im.com
DC Bead and DC Bead LUMI are trademarks of Biocompatibles UK Ltd, a
BTG International group company. BTG and the BTG roundel logo are
registered trademarks of BTG International Ltd in the US, EU and
certain other territories, and are trademarks of BTG International Ltd
elsewhere.
CN 00911.2
Page 22 of 22