Merit Medical HepaSphere Microspheres(With Doxorubicin) IFU- Canada - Manuel

HEPASPHERE MICROSPHERES CAN BE USED WITH OR WITHOUT LOADING OF DOXORUBICIN HCL.
OPTION 1: PREPARATION FOR EMBOLIZATION WITHOUT DOXORUBICIN HCL (BLAND)
The approximate reconstitution time when used without loading of doxorubicin HCl is 10 min.
• Fill a 10ml syringe with 100% NaCl 0.9% aqueous solution or non-ionic contrast medium
(or 50% NaCl 0.9% aqueous solution and 50% contrast). Connect the syringe to a needle of
20 gauge diameter or larger.
• To ensure proper reconstitution of the HepaSphere Microspheres, grasp the vial horizontally
in your fingertips and roll the vial several times. This will transfer the dry contents of the vial
to the sidewall.
Note: Pull back only the flip-top cap; do not remove the crimp ring or the stopper from the vial.
• Carefully insert the needle from the syringe through the stopper of the vial. Continue rolling
the vial in your fingertips and inject the full amount (10ml) of reconstitution medium into the
vial, then place the vial vertically and carefully remove the syringe with the needle attached.
Note: The vial is hermetically closed. Proper aspiration and/or venting techniques, as approved
by the healthcare facility, may be used for easier injection of reconstitution medium into vial.
If aspiration of air from the vial is performed prior to reconstitution, exercise caution not to
remove the spheres from the vial.
• To ensure a homogeneous reconstitution of the HepaSphere Microspheres, gently invert the
vial back and forth so that the liquid contacts the stopper 5-10 times.
Note: Vigorous shaking may introduce micro bubbles, which can cause the microspheres
to aggregate.
• Wait a minimum of 10 minutes to allow the HepaSphere Microspheres to reconstitute and
expand fully.
• Use a 30ml syringe and 20 gauge or larger needle to aspirate the contents of the vial. Rotate
the vial to a vertical position with the bottom of the vial facing upward. Pull the needle back
so that it is submerged in the liquid but not occluded by the stopper. Gently aspirate the
entire contents of the vial into the syringe.
Note: If the air was previously aspirated from the vial, gentle injection of air using the syringe
prior to aspirating the contents of the vial will ensure an easier aspiration of vial contents into
the syringe. If all contents are not withdrawn, introduce an additional volume of air and repeat
the aspiration process. It is possible to add an additional amount of non-ionic contrast or NaCl
0.9% aqueous solution into the syringe in order to get a higher dispersion of microspheres.
Note: HepaSphere Microspheres reconstituted as described above can be used in the presence
of chemotherapeutic agents such as cisplatin, epirubicin, doxorubicin HCl, fluorouracil,
irinotecan and mitomycin after hydration. However for drug delivery, HepaSphere
Microspheres are only indicated for use with doxorubicin HCl (see below Option 2).
• If microspheres were reconstituted using 100% NaCl 0.9%, non-ionic contrast medium must
be added to the syringe containing the HepaSphere Microspheres for visualization under
fluoroscopy. If non-ionic contrast medium was used to reconstitute the microspheres,
additional non-ionic contrast medium may be added.
OPTION 2: PREPARATION FOR EMBOLIZATION LOADED WITH DOXORUBICIN HCL
WARNING: Liposomal formulations of doxorubicin HCl are not suitable for loading into Hepa-
Sphere Microspheres.
As a general guideline the loading of lyophilized doxorubicin HCl solubilized in NaCl 0.9% solu-
tion into HepaSphere Microspheres will take one hour. The HepaSphere Microspheres should
not be used before they are fully hydrated and expanded. Loading kinetics of pre-solubilized
doxorubicin HCI may vary, depending on the concentration and pH of the solution.
• Choose the appropriate dose of doxorubicin HCl to load into the HepaSphere Microspheres.
Note: A maximum dose of doxorubicin HCl 75mg can be loaded into each vial of HepaSphere
Microspheres. Solubilize the desired dose of lyophilized doxorubicin HCl in 20ml of NaCl 0.9%
solution for injection. NEVER USE PURE WATER
Note: Maximum recommended concentration of doxorubicin HCl is 5mg/ml. Concentrations of
doxorubicin HCl above 5mg/ml substantially increase the solution viscosity and make it
difficult to handle with HepaSphere Microspheres.
• Aspirate the 20ml of doxorubicin HCl solution into two separate 30ml syringes. Each 30ml
syringe should contain 10ml of doxorubicin HCl solution.
• Connect one of the 30ml syringes containing 10ml of the doxorubicin HCl solution to a needle
of 20 gauge diameter or larger.
• To ensure proper reconstitution of the HepaSphere Microspheres, grasp the HepaSphere
Microspheres vial horizontally in your fingertips and roll the vial several times. This will transfer
the dry contents of the vial to the sidewall.
Note: Pull back only the flip-top cap; do not remove the crimp ring or the stopper from the vial.
• Carefully insert the needle of one of the 30ml syringes containing 10ml of doxorubicin HCl
solution through the stopper of the vial. Continue rolling the vial in your fingertips and inject
the full 10ml of doxorubicin HCl solution into the vial.
• Place the HepaSphere Microspheres vial vertically. Carefully remove the syringe with the
needle attached, and allow the vial to stand for 10 minutes in order to completely hydrate
the spheres.
• During the 10 minutes hydration period, shake the HepaSphere Microspheres vial several
times back and forth so that the liquid contacts the grey stopper. Repeat this process every
2-3 minutes to ensure a homogenous reconstitution of the HepaSphere Microspheres.
Note: The vial is hermetically closed. Proper aspiration and/or venting techniques, as approved
by the healthcare facility, may be used for easier injection of reconstitution media into the
vial. If aspiration of air from the vial is performed prior to reconstitution, exercise caution not
to remove the spheres from the vial.
• After the 10 minutes hydration period, attach a 20 gauge or larger needle to the second
30ml syringe containing the remaining 10ml of doxorubicin HCl solution and insert into the
HepaSphere Microspheres vial. Aspirate the contents of the HepaSphere Microspheres vial
into the 30ml syringe containing the remaining 10 ml of doxorubicin HCl solution. Rotate
the vial to a vertical position with the bottom of the vial facing upward. Pull the needle back
so that it is submerged in the liquid but not occluded by the stopper. Gently aspirate the
entire contents of the vial into the syringe.
• Prior to removing the needle from the HepaSphere Microspheres vial, while holding the
syringe vertically, gently pull the plunger of the syringe down, removing any solution that
may be in the hub of the needle.
• Replace the needle with a syringe cap and invert the syringe back and forth to disperse the
contents within the syringe. Wait a minimum of 60 minutes to allow the HepaSphere
Microspheres to expand fully and load the doxorubicin HCl. During the 60 minutes, the
syringe should be inverted every 10 – 15 minutes in order to optimize the drug distribution
into the spheres.
• After 60 minutes, let the syringe stand for the spheres to settle down and purge all
supernatant and discard it following facility approved standards.
• Add a minimum of 20ml of non-ionic contrast medium to the 30ml syringe containing the
doxorubicin HCl loaded HepaSphere Microspheres, however larger volume of solution can
provide better control during embolization. Gently invert the syringe 2 or 3 times and wait
5 min until solution homogeneity is reached.
• Before any injection, check the spheres are in suspension, if not invert the syringe back and
forth to disperse contents within the syringe.
PRECAUTIONS:
HepaSphere Microspheres must only be used by physicians trained in vascular embolization
procedures. The size and quantity of microspheres must be carefully selected according to the
lesion to be treated and the potential presence of shunts. Only the physician can decide the
most appropriate time to stop the injection of HepaSphere Microspheres.
Do not use if the vial, cap, or pouch appear damaged.
For single patient use only - Contents supplied sterile - Never reuse, reprocess, or resterilize the
contents of a vial that has been opened. Reusing, reprocessing or resterilizing may compromise
the structural integrity of the device and or lead to device failure, which in turn may result in
patient injury, illness or death. Reusing, reprocessing or resterilizing may also create a risk of
contamination of the device and or cause patient infection or cross infection including, but not
limited to, the transmission of infectious disease(s) from one patient to another. Contamina-
tion of the device may lead to injury, illness or death of the patient. All procedures must be
performed according to accepted aseptic technique.
HepaSphere Microspheres MUST NOT be used in their original dry state. They must be re-
constituted before use. HepaSphere Microspheres swell in aqueous solution. The magnitude of
swelling depends on the ionic concentration of the solution. The microspheres swell to approxi-
mately four times their diameter in 0.9% NaCl aqueous solution and non-ionic contrast media,
as compared to their initial dry diameter. The magnitude of swelling when loaded with doxoru-
bicin HCl is dependent upon the amount of drug with which the product is loaded. Lyophilized
doxorubicin HCl must be reconstituted in NaCl 0.9 % solution. HepaSphere Microspheres un-
dergo a slight size decrease of about 20% when loaded with doxorubicin HCl compared to the
size in pure NaCl 0.9 % aqueous solution. HepaSphere Microspheres are compressible and can
be injected easily through microcatheters. However, injection of the HepaSphere Microspheres
before they are fully expanded could result in failure to reach the intended embolization target
and possible embolization of a larger tissue area.
Note: Maximum recommended concentration of doxorubicin HCl is 5mg/ml. Concentrations of
doxorubicin HCl above 5mg/ml substantially increase the solution viscosity and make it difficult
to handle with HepaSphere Microspheres.
Patients with known allergies to non-ionic contrast media may require corticosteroids prior to
embolization.
Additional evaluations or precautions may be necessary in managing periprocedural care for
patients with the following conditions:
• Bleeding diathesis or hypercoagulative state
• Immunocompromise
POTENTIAL COMPLICATIONS:
Vascular embolization is a high-risk procedure. Complications may occur at any time during or
after the procedure, and may include, but are not limited to, the following:
• Paralysis resulting from untargeted embolization or ischemic injury from adjacent
tissue oedema
• Undesirable reflux or passage of HepaSphere Microspheres into normal arteries adjacent to
the targeted lesion or through the lesion into other arteries or arterial beds, such as the
internal carotid artery, pulmonary, or coronary circulation
• Pulmonary embolism due to arteriovenous shunting
• Ischemia at an undesired location, including ischemic stroke, ischemic infarction (including
myocardial infarction), and tissue necrosis
• Capillary bed occlusion and tissue damage
• Vasospasm
• Recanalisation
• Blindness, hearing loss, and loss of smell
• Foreign body reactions necessitating medical intervention
• Infection necessitating medical intervention
• Complications related to catheterization (e.g. haematoma at the site of entry, clot formation
at the tip of the catheter and subsequent dislodgement, and nerve and/or circulatory injuries
which may result in leg injury)
• Allergic reaction to medications (e.g. analgesics)
• Allergic reaction to non-ionic contrast media or embolic material
• Vessel or lesion rupture and haemorrhage
• Death
• Additional information is found in the Warnings section
SWELLING BEHAVIOR:
HepaSphere Microspheres swell during reconstitution with NaCl 0.9% aqueous solution and
non-ionic contrast media. When hydrated in 100% NaCl 0.9% aqueous solution or non-ionic
contrast medium, or 50% non-ionic contrast and 50% NaCl 0.9% aqueous solution, HepaSphere
Microspheres swell approximately 4 times their original dry diameter in approximately 10
minutes. For example, HepaSphere Microspheres with a diameter of approximately 50-100
microns in their dry state will expand to approximately 200-400 microns during reconstitution
as recommended below. Because of the inherent variability of the swelling process, some of
the HepaSphere Microspheres will be slightly outside of this range after reconstitution, so the
physician should be sure to carefully select the size of HepaSphere Microspheres according to
the size of the target vessels at the desired level of occlusion in the vasculature and the nature
of the aqueous solution.
Note: To expand properly HepaSphere Microspheres need to be exposed to a minimum of 10ml
solution.
The magnitude of swelling when loaded with doxorubicin HCl is dependent upon the amount
of drug with which the product is loaded. HepaSphere Microspheres undergo a slight size
decrease of about 20% when loaded with doxorubicin HCl compared to the size in pure NaCl
0.9% aqueous solution.
CATHETER COMPATIBILITY:
HepaSphere Microspheres can be injected with microcatheters with the following specifications:
Dry (μm) Approximate Reconstituted Size range (μm) Catheter Size ID (in.)
3 0 - 6 0 1 2 0 - 2 4 0 ≥ 0 . 0 2 1
5 0 - 1 0 0 2 0 0 - 4 0 0 ≥ 0 . 0 2 1
1 0 0 - 1 5 0 4 0 0 - 6 0 0 ≥ 0 . 0 2 4
1 5 0 - 2 0 0 6 0 0 - 8 0 0 ≥ 0 . 0 2 7
INSTRUCTIONS:
HepaSphere Microspheres must be reconstituted with 100% NaCl 0.9% aqueous solution or
non-ionic contrast medium, or 50% non-ionic contrast medium and 50% NaCl 0.9% aqueous
solution if using without delivery of doxorubicin HCl, or loaded with doxorubicin HCl solution
before positioning the catheter.
• Carefully select the size of HepaSphere Microspheres according to the size of the target
vessels at the desired level of occlusion in the vasculature and the nature of the aqueous s
olution. See the description of “SWELLING BEHAVIOR”.
• HepaSphere Microspheres may be present outside the vial. Therefore, the vial must be
aseptically handled away from the main sterile field.
• Ensure the compatibility of the HepaSphere Microspheres with the intended size of catheter
to be used. See the table above.
• Inspect the packaging to confirm that it is intact. Remove the vial from the pouch.
The external surface of the vial is sterile.
ENGLISH
INTENDED USE:
HepaSphere™ Microspheres without doxorubicin HCl loaded (bland) are indicated for use
in embolization of blood vessels for therapeutic or preoperative purposes in the following
procedures:
• Embolization of hepatocellular carcinoma
• Embolization of metastases to the liver.
HepaSphere Microspheres loaded with doxorubicin HCl are indicated for use in embolization of
blood vessels for therapeutic or preoperative purposes in:
Embolization of unresectable hepatocellular carcinoma.
DESCRIPTION:
HepaSphere Microspheres are part of a family of embolic agents based on proprietary technolo-
gies. They are designed for controlled, targeted embolization. The HepaSphere Microspheres
can be loaded with doxorubicin HCl and are able to release the drug locally at the embolization
site. HepaSphere Microspheres are biocompatible, hydrophilic, non-resorbable, expandable,
and conformable microspheres. HepaSphere Microspheres swell upon exposure to aqueous
solutions. They are available in a range of sizes.
D r y
( μ m )
3 0 - 6 0
5 0 - 1 0 0
1 0 0 - 1 5 0
1 5 0 - 2 0 0
DEVICE PACKAGING:
HepaSphere Microspheres are contained in a sterile, 10 ml Cyclic Olefin Copolymers (COC) vial,
with a crimped cap, packaged in a sealed pouch.
Contents: 25 mg or 50 mg of dry HepaSphere Microspheres per vial to be reconstituted before
use.
CONTRAINDICATIONS:
• Patients intolerant to vascular occlusion procedures
• Vascular anatomy or blood flow precluding correct catheter placement or embolic injection
• Presence or suspicion of vasospasm
• Presence or likely onset of haemorrhage
• Presence of severe atheromatous disease
• Feeding arteries too small to accept the selected HepaSphere Microspheres
• Presence of collateral vessel pathways potentially endangering normal territories
during embolization
• High flow arteriovenous shunts or fistulae with luminal diameter greater than the selected
size of HepaSphere Microspheres
• Vascular resistance peripheral to the feeding arteries precluding passage of HepaSphere
Microspheres into the lesion
• Presence of arteries supplying the lesion not large enough to accept HepaSphere
Microspheres
• Do not use in pulmonary vasculature, coronary and central nervous system vasculature
• Known sensitivity to poly vinyl alcohol-co-sodium acrylate
WARNINGS:
• HepaSphere Microspheres size must be chosen after consideration of the arteriovenous
angiographic appearance. HepaSphere Microspheres size should be selected to prevent
passage from any artery to vein.
• Some of the HepaSphere Microspheres may be slightly outside of the range, so the physician
should be sure to carefully select the size of HepaSphere Microspheres according to the size of
the target vessels at the desired level of occlusion in the vasculature and after consideration of
the arteriovenous angiographic appearance.
• Because of the significant complications of misembolization, extreme caution should be used
for any procedures involving the extracranial circulation encompassing the head and neck,
and the physician should carefully weigh the potential benefits of using embolization against
the risks and potential complications of the procedure. These complications can include
blindness, hearing loss, loss of smell, paralysis, and death. Safety and effectiveness of this
device for use involving the extracranial circulation encompassing the head and neck or any
other part of the body other than the liver has not been established and has therefore not
been approved by Health Canada.
• Serious radiation induced skin injury may occur to the patient due to long periods of
fluoroscopic exposure, large patient, angled x-ray projections and multiple image recording
runs or radiographs. Refer to your facility’s clinical protocol to ensure the proper radiation
dose is applied for each specific type of procedure performed.
• Onset of radiation injury to the patient may be delayed. Patients should be counselled on
potential radiation effects, what to look for and who to contact if symptoms occur.
• HepaSphere Microspheres MUST NOT be reconstituted in sterile water for injection.
Reconstitution in sterile water results in extensive swelling that renders the injection of
HepaSphere Microspheres very difficult or may prevent injection.
• Do not reconstitute HepaSphere Microspheres with Lipiodol / Ethiodol.
• Pay careful attention for signs of mistargeted embolization. During injection carefully
monitor patient vital signs to include SAO2 (e.g. hypoxia, CNS changes). Consider terminating
the procedure, investigating for possible shunting, or increasing Microspheres size if any signs
of mistargeting occur or patient symptoms develop.
• Consider upsizing the Microspheres if angiographic evidence of embolization does not
quickly appear evident during injection of the Microspheres.
• See product monograph for Health Canada authorized indications for use for doxorubicin
HCl. Information herein is specifically for the use of HepaSphere Microspheres with or without
doxorubicin HCl.
Warnings about use of small microspheres:
• Careful consideration should be given whenever use is contemplated of embolic agents that
are smaller in diameter than the resolution capability of your imaging equipment. The
presence of arteriovenous anastomoses, branch vessels leading away from the target area or
emergent vessels not evident prior to embolization can lead to mistargeted embolization and
severe complications.
• Microspheres smaller than 100 microns will generally migrate distal to anastomotic feeders
and therefore are more likely to terminate circulation to distal tissue. Greater potential of
ischemic injury results from use of smaller sized microspheres and consideration must be
given to the consequence of this injury prior to embolization. The potential consequences
include swelling, necrosis, paralysis, abscess and/or stronger post-embolization syndrome.
• Post embolization swelling may result in ischemia to tissue adjacent to target area. Care must
be given to avoid ischemia of intolerant, non targeted tissue such as nervous tissue.
730133002/A ID 103112 0459-2004
DELIVERY INSTRUCTIONS:
• Carefully evaluate the vascular network associated with the target lesion utilizing high
resolution imaging.
Note: It is important to determine if any arteriovenous shunts are present before beginning
embolization.
• Using standard techniques, position the delivery catheter within the target vessel and the
catheter tip as close as possible to the embolization target.
• Use an injection syringe no larger than 3ml for the delivery of doxorubicin loaded HepaSphere
Microspheres. Use of a 1ml injection syringe is recommended.
• Aspirate 1ml of the HepaSphere Microspheres mixture into the injection syringe.
• Two methods for embolic aliquot sequestering for injection may be used:
Option 1: Connect a 3 way-stopcock to the 30ml syringe containing the doxorubicin
loaded HepaSphere Microspheres to the infusion micro catheter and use a 1ml syringe for
injection through the open port of the 3 way-stopcock.
Option 2: Serial aliquots of the doxorubicin loaded HepaSphere Microspheres can be
drawn from the 30ml syringe into a 1ml injection syringe through a 3 way-stop cock that is
not attached to the infusion catheter. The 1ml syringe containing each aliquot can be
attached independently to the infusion microcatheter and injected.
• Invert the 30ml syringe back and forth to maintain the homogenous suspension of the
HepaSphere Microspheres mixture.
• Under continuous fluoroscopic guidance, inject the aliquot of doxorubicin loaded
HepaSphere Microspheres in a slow, non forceful, pulsatile manner over a time period of
approximately 1 minute per ml of microspheres solution. Always inject under free-flow
conditions and monitor for reflux.
Note: Reflux of embolic spheres can induce immediate ischemia of untargeted tissues
and vessels.
• When stasis in the feeding pedicle occurs while delivering the doxorubicin HCl loaded
HepaSphere Microspheres, wait a minimum of 5 minutes then perform a selective angiogram
after the full 5 minutes wait to verify the cessation of antegrade flow.
• If cessation of antegrade flow has not occurred, continue infusion under fluoroscopic
guidance until the desired devascularization is obtained.
• After the HepaSphere Microsphere infusion is completed, remove the catheter while
maintaining gentle aspiration to avoid dislodging any residual HepaSphere Microspheres
that may still be in the catheter lumen. Discard the catheter after removal and do not reuse.
• Discard any open vial or unused HepaSphere Microspheres.
CAUTION:
In the event that the catheter becomes obstructed or significant infusion resistance is encoun-
tered during injection, do not attempt to flush the catheter with excessive pressure because
reflux of embolic material may occur resulting in untargeted embolization. Remove the catheter
while applying gentle aspiration and discard.
CONSERVATION AND STORAGE:
HepaSphere Microspheres must be stored in a dry, dark place in their original vials and packag-
ing. Use by the date indicated on the labels of the outer box and pouch.
When the procedure of reconstitution is completed, store the solution of HepaSphere Micro-
spheres in 2 to 8°C conditions and use within 24 hours, IF not used immediately. Do not store
HepaSphere Microspheres after contrast medium has been added.
Size of dry Colour code Quantity of
products (µm) (label borders) microspheres (mg) Reference
3 0 - 6 0 O r a n g e 2 5 V 2 2 5 H S
5 0 V 2 5 0 H S
5 0 - 1 0 0 Ye l l o w 2 5 V 3 2 5 H S
5 0 V 3 5 0 H S
1 0 0 - 1 5 0 B l u e 2 5 V 5 2 5 H S
5 0 V 5 5 0 H S
1 5 0 - 2 0 0 R e d 2 5 V 7 2 5 H S
5 0 V 7 5 0 H S
INFORMATION ON PACKAGING:
Symbol Designation
Manufacturer: Name & Address
Use by date: year-month
Batch code
Catalogue number
Do not resterilize
Do not use if package is damaged
Keep away from sunlight
Keep dry
Do not re-use
Caution - Refer to Instructions For Use
Non-pyrogenic
Sterilized using irradiation
EC mark logo - Notified body identification : 0459
• /
•
Size of dry microspheres / Size of hydrated microspheres
All serious or life threatening adverse events or deaths associated with use of HepaSphere
Microspheres should be reported to the device manufacturer.
Biosphere Medical, S.A.
Parc des Nations - Paris Nord 2
383 rue de la Belle Etoile
95700 Roissy en France
France
Tel: +33 (0) 1 48 17 25 25
Fax: +33 (0) 1 49 38 02 68