•
When treating multiple lesions within the same vessel, stent the distal lesion prior
to stenting the proximal lesion. Stenting in this order obviates the need to cross
the proximal stent during placement of the distal stent, and reduces the chance of
damaging or dislodging the proximal stent.
•
When multiple DES stents are required, only stent material with similar composition
(e.g. XIENCE Everolimus Eluting Coronary family Stents with the identical cobalt-
chro,mium stent substrate and identical drug-eluting polymer coating) should be
used. Potential interaction with other drug-eluting stents or coated stents has not
been evaluated, and should be avoided. Placing multiple stents of different metals
in contact with each other may increase the potential for corrosion
in vivo
, although
in vitro
corrosion tests using an L-605 CoCr alloy stent in combination with a 316L
stainless steel alloy stent did not appear to increase corrosion.
•
The extent of the patient’s exposure to drug and polymer is directly related to the
number of stents implanted. A patient can receive up to four XIENCE Sierra Everolimus
Eluting Coronary Stents or other everolimus eluting coronary stents from the XIENCE
family (i.e., XIENCE V, XIENCE PRIME, XIENCE Xpedition, XIENCE Alpine) depending on
the number of vessels treated and the lesion length. Those patients receiving bailout
stenting will receive additional XIENCE family stents. The use of multiple XIENCE family
stents will result in the patient receiving larger amounts of drug and polymer.
•
The safety and effectiveness of the XIENCE Sierra Everolimus Eluting Coronary Stent
in patients with prior brachytherapy of the target lesion or the use of brachytherapy
for treated site restenosis in a XIENCE Sierra Everolimus Eluting Coronary family
stent have not been established. Both vascular brachytherapy and the XIENCE Sierra
Everolimus Eluting Coronary family stents alter arterial remodeling. The potential
combined effect on arterial remodeling by these two treatments is not known.
5.3 Use in Conjunction with Other Procedures
•
While vessel preparation in complex lesions may include the use of various
mechanical atherectomy devices,the safety and effectiveness of the XIENCE Sierra
stents have not been established in clinical trials with use of either mechanical
atherectomy devices (directional atherectomy catheters, rotational atherectomy
catheters) or laser angioplasty catheters.
5.4 Stent / System Removal
• Stent delivery system removal prior to stent deployment:
If removal of a stent system is required prior to deployment, ensure that the guide
catheter is coaxially positioned relative to the stent delivery system, and cautiously
withdraw the stent delivery system into the guiding catheter. Should unusual
resistance be felt at any time when withdrawing the stent into the guide catheter, the
stent delivery system and the guide catheter should be removed as a single unit. This
should be done under direct visualization with fluoroscopy.
• Withdrawal of the stent delivery system / post-dilatation balloon from the deployed
stent:
1. Deflate the balloon by pulling negative on the inflation device. Larger and longer balloons
will take more time (up to 30 seconds) to deflate than smaller and shorter balloons.
Confirm balloon deflation under fluoroscopy and wait 10 – 15 seconds longer.
2. Position the inflation device to “negative” or “neutral” pressure.
3. Stabilize guide catheter position just outside coronary ostium and anchor in place.
Maintain guide wire placement across stent segment.
4. Gently remove the stent delivery system / post-dilatation balloon with slow and steady
pressure.
5. Tighten the rotating hemostatic valve.
Notes:
1) If during withdrawal of the catheter from the deployed stent, resistance is
encountered, use the following steps to improve balloon rewrap:
o
Re-inflate the balloon up to nominal pressure.
o
Repeat steps 1 through 5 above.
2) After successful withdrawal of the balloon from the deployed stent, should any
resistance be felt at any time when withdrawing the stent delivery system or post-
dilatation balloon into the guide catheter, remove the entire system as a single unit.
•
Failure to follow these steps and / or applying excessive force to the delivery
system can potentially result in loss or damage to the stent and / or delivery system
components.
•
If it is necessary to retain guide wire position for subsequent artery / lesion access,
leave the guide wire in place and remove all other system components.
5.5 Post Implant
•
If necessary to cross a newly deployed stent with a guide wire, balloon, delivery
system, or imaging catheters, exercise care to avoid disrupting the stent geometry.
•
Subsequent restenosis may require repeat dilatation of the arterial segment
containing the stent. The long-term outcome following repeat dilatation of stents is
unknown at present.
•
If the patient requires imaging, see
Section 5.7 Magnetic Resonance Imaging (MRI)
Safety Information.
5.6 Use in Special Populations
5.6.1 Pregnancy
Pregnancy Category C: see
Section 6.2 Pregnancy.
This product has not been tested in
pregnant women or in men intending to father children. Effects on the developing foetus
have not been studied. Effects of a XIENCE V on pre-natal and post-natal rat development
were no different than the controls. When administered at oral doses of 0.1 mg/kg or above
to animals, everolimus has shown reproductive toxicity effects including embryo toxicity and
foetotoxicity
1
. Effective contraception is recommended to be initiated before implanting and
continued for one year after implantation. While there is no contraindication, the risks and
reproductive effects are unknown at this time
1
.
5.6.2 Lactation
See
Section 6.3 Lactation
. It is unknown whether everolimus is distributed in human milk. A
decision should be made whether or not to discontinue nursing prior to stent implantation,
considering the importance of the stent to the mother.
5.6.3 Pediatric use
The safety and effectiveness of the XIENCE Sierra stent in pediatric subjects have not been
established.
1
Certican
®
UK label Mar 2015, Afinitor
®
EU authorization SPC Dec 2014, Votubia
®
EU SPC
Sept 2014, Afinitor
®
US label Jan 2015, and Zortress
®
US label Sept 2015. Refer to
www.MHRA.gov.uk, www.ema.europa.eu, and www.fda.gov for the most recent versions
of these SPC/labels.
5.7 Magnetic Resonance Imaging (MRI) Safety Information
Non-clinical testing has demonstrated that the XIENCE Sierra stent, in single and in
overlapped configurations up to 71 mm in length, are MR Conditional. A patient with this
device can be scanned in an MR system under the following conditions:
•
Static magnetic field of 1.5 or 3 Tesla
•
Maximum Spatial gradient field of 3000 Gauss/cm
•
Maximum MR System reported whole-body-averaged specific absorption rate (SAR)
of 2.0 W/kg (normal operating mode)
Under the scan conditions defined above, the XIENCE Sierra stents are expected to produce
a maximum temperature rise of less than 4.5ºC after 15 minutes of continuous scanning.
In non-clinical testing, the image artifact caused by the device extends approximately
6 mm from the XIENCE Sierra stent when imaged with a gradient echo or spin echo pulse
sequence and a 3T MRI system.
5.8 Drug Interactions
See
Section 6.1 Interactions with Drugs or Other Substances
. Several drugs are known
to affect everolimus metabolism, and other drug interactions may also occur. Everolimus
is known to be a substrate for both cytochrome P4503A4 (CYP3A4) and P-glycoprotein
(PgP). Everolimus absorption and subsequent elimination may be influenced by drugs that
affect these pathways. Everolimus has also been shown to reduce the clearance of some
prescription medications when administered orally along with cyclosporine (CsA). Formal
drug interaction studies have not been performed with the XIENCE Sierra stent because of
limited exposure to everolimus eluted from the stent. Therefore, due consideration should be
given to the potential for both systemic and local drug interactions in the vessel wall, when
deciding to place the XIENCE Sierra stent in a patient taking a drug with known interaction
with everolimus, or when deciding to initiate therapy with such a drug in a patient who has
recently received the XIENCE Sierra stent.
5.9 Immune Suppression Potential
Everolimus, the XIENCE Sierra stent active ingredient, is an immunosuppressive agent.
Immune suppression was not observed in the SPIRIT and XIENCE family of clinical trials.
However, for patients who receive several XIENCE Sierra devices simultaneously, it may be
possible for everolimus systemic concentrations to approach immunosuppressive levels
temporarily, especially in patients who also have hepatic insufficiency or who are taking
drugs that inhibit CYP3A4 or P-glycoprotein. Therefore, consideration should be given to
patients taking other immunosuppressive agents or who are at risk for immune suppression.
5.10 Lipid Elevation Potential
Oral everolimus use in renal transplant and advanced renal cell carcinoma patients was
associated with increased serum cholesterol and triglyceride levels, which in some cases
required treatment. The effect was seen with both low and high dose prolonged oral
therapy in a dose related manner. When used according to the indications for use, exposure
to systemic everolimus concentrations from the XIENCE Sierra stent is expected to be
significantly lower than concentration exposure usually obtained in transplant patients.
Increased serum cholesterol and triglyceride levels were not observed in the SPIRIT and
XIENCE family of clinical trials. Oral administration of everolimus in combination with
cyclosporine has been associated with increased serum cholesterol and triglyceride levels.
6.0 DRUG INFORMATION
6.1 Interactions with Drugs or Other Substances
Everolimus is extensively metabolized by the cytochrome P4503A4 (CYP3A4) in the gut
wall and liver, and is a substrate for the countertransporter P-glycoprotein. Everolimus has
also been shown to reduce the clearance of some prescription medications when it was
administered orally along with cyclosporine (CsA). Hence, everolimus, when prescribed as
an oral medication, may interact with other medications that include (but are not restricted
to) inhibitors and inducers of CYP3A4 isozymes; absorption and subsequent elimination of
everolimus may be influenced by drugs that affect these pathways. Formal drug interaction
studies have not been performed with the XIENCE Sierra or XIENCE V stents because of
limited systemic exposure to everolimus eluted from XIENCE V. However, consideration
should be given to the potential for both systemic and local drug interactions in the vessel
wall when deciding to place the XIENCE Sierra stent in a subject taking a drug with known
interaction with everolimus.
Everolimus, when prescribed as an oral medication, may interact with the following drugs
or foods
1
:
•
CYP3A4 / P-glycoprotein isozyme inhibitors
o
Antifungal agents (e.g., fluconazole, ketoconazole, itraconazole, posaconazole,
voriconazole)
o
Macrolide antibiotics (e.g., erythromycin, clarithromycin, telithromycin)
o
Calcium channel blockers (e.g., verapamil, nicardipine, diltiazem)
o
Protease inhibitors (e.g., ritonavir, atazanavir, saquinavir, darunavir, indinavir,
nelfinavir, amprenavir, fosamprenavir)
o
Other (e.g., cyclosporine, nefazodone, cisapride, metoclopramide,
bromocriptine, cimetidine, danazol, sildenafil, terfenadine, astemizole,
grapefruit / grapefruit juice, digoxin)
•
CYP3A4 / P-glycoprotein isozyme inducers
o
Antibiotics (e.g., rifampin, rifabutin, ciprofloxacin, ofloxacin)
o
Anticonvulsants (e.g., carbamazepine, phenobarbital, phenytoin)
o
Non-nucleoside reverse transcriptase inhibitors (e.g., efavirenz, nevirapine)
o
Glucocorticoids (e.g., dexamethasone, prednisone, prednisolone)
o
HMGCoA reductase inhibitors (simvastatin, lovastatin)
o
Other (e.g., St. John’s Wort)
For more detailed drug interaction information, please reference the most recent everolimus
drug label
1
.
6.2 Pregnancy
Pregnancy Category C: There are no adequate everolimus or XIENCE Sierra stent-related
studies in pregnant women. Effects of a similar stent, XIENCE V, on pre-natal and post-natal
rat development were no different than the controls. When administered at oral doses of
0.1 mg/kg or above to animals, everolimus has shown reproductive toxicity effects including
embryotoxicity and foetotoxicity
1
. Effective contraception is recommended to be initiated
before implanting a XIENCE Sierra stent and continued for one year post-implantation. The
XIENCE Sierra stent should be used in pregnant women only if potential benefits of the stent
outweigh potential risks.
The safety of the XIENCE Sierra stent has not been evaluated in males intending to father
children.
6.3 Lactation
It is unknown whether everolimus is distributed in human milk. Also, everolimus
pharmacokinetic and safety profiles have not been determined in infants. Consequently,
mothers should be advised of potential serious adverse reactions to everolimus in nursing
infants. Prior to XIENCE Sierra stent implantation, decisions should be made regarding
whether to discontinue nursing or conduct an alternate percutaneous coronary intervention
procedure.
7.0 POTENTIAL ADVERSE EVENTS
Adverse events that may be associated with PCI treatment procedures and the use of a
stent in native coronary include, but are not limited to, the following:
•
Allergic reaction or hypersensitivity to latex, contrast agent, anesthesia, device
materials (cobalt, chromium, nickel, tungsten, acrylic, and fluoropolymers), and drug
reactions to everolimus, anticoagulation, or antiplatelet drugs
•
Vascular access complications which may require transfusion or vessel repair,
including:
o
Catheter site reactions
o
Bleeding (ecchymosis, oozing, hematoma, hemorrhage, retroperitoneal
hemorrhage)
o
Arteriovenous fistula, pseudoaneurysm, aneurysm, dissection,
perforation / rupture
o
Embolism (air, tissue, plaque, thrombotic material or device)
o
Peripheral nerve injury
o
Peripheral ischemia
•
Coronary artery complications which may require additional intervention, including:
o
Total occlusion or abrupt closure
o
Arteriovenous fistula, pseudoaneurysm, aneurysm, dissection,
perforation / rupture
o
Tissue prolapse / plaque shift
o
Embolism (air, tissue, plaque, thrombotic material, or device)
o
Coronary or stent thrombosis (acute, subacute, late, very late)
o
Stenosis or restenosis.
•
Pericardial complications which may require additional intervention, including:
o
Cardiac tamponade
o
Pericardial effusion
o
Pericarditis
•
Cardiac arrhythmias (including conduction disorders, aspecific, atrial and ventricular
arrhythmias) Cardiac ischemic conditions (including myocardial ischemia, myocardial
infarction (including acute), coronary artery spasm, and unstable or stable angina
pectoris)
•
Stroke / cerebrovascular accident (CVA) and Transient Ischemic Attack (TIA)
•
System organ failures:
o
Cardio-respiratory arrest
o
Cardiac failure
o
Cardiopulmonary failure (including pulmonary edema)
o
Renal Insufficiency / failure
o
Shock
•
Blood cell disorders (including Heparin Induced Thrombocytopenia [HIT])
•
Hypotension / hypertension
•
Infection
•
Nausea and vomiting
•
Palpitations, dizziness, and syncope
•
Chest pain
•
Fever
•
Pain
•
Death
Adverse events associated with daily oral administration of everolimus in doses varying
from 1.5 mg to 10 mg daily can be found in the Summary of Product Characteristics
(SPC) and labels for the drug
1
. The risks described below include the anticipated adverse
events relevant for the cardiac population referenced in the contraindications, warnings and
precaution sections of the everolimus labels / SPCs and / or observed at incidences ≥ 10%
in clinical trials with oral everolimus for different indications. Please refer to the drug SPCs
and labels for more detailed information and less frequent adverse events:
•
Abdominal pain
•
Anemia
•
Angioedema (increased risk with concomitant ACE inhibitor use)
•
Arterial thrombotic events
•
Bleeding and coagulopathy (including Hemolytic Uremic Syndrome [HUS],
Thrombotic Thrombocytopenic Purpura [TTP], and thrombotic microangiopathy –
increased risk with concomitant cyclosporine use)
•
Constipation
•
Cough
•
Diabetes mellitus
•
Diarrhea
•
Dyspnea
•
Embryo-fetal toxicity
•
Erythema
•
Erythroderma
•
Headache
•
Hepatic Artery Thrombosis (HAT)
•
Hepatic disorders (including hepatitis and jaundice)
•
Hypersensitivity to everolimus active substance, or to other rapamycin derivates
•
Hypertension
•
Infection (bacterial, fungal, viral or protozoan infections, including infections with
opportunistic pathogens). Polyoma virus-associated nephropathy (PVAN) JC virus
associated progressive multiple leukoencephalopathy (PML), fatal infections and
sepsis have been reported in patients treated with oral everolimus.
•
Kidney arterial and venous thrombosis
•
Laboratory test alterations (elevations of serum creatinine, proteinuria, hypokalemia;
hyperglycemia, dyslipidemia including hypercholesterolemia and hypertriglyceridemia;
abnormal liver function tests; decreases in hemoglobin, lymphocytes, neutrophils,
and platelets)
•
Lymphoma and skin cancer
•
Nausea
•
Nephrotoxicity (in combination with cyclosporine)
•
Non-infectious pneumonitis (including interstitial lung disease)
•
Oral ulcerations
•
Pain
•
Pancreatitis
•
Pericardial effusion
•
Peripheral edema
•
Pleural effusion
EL2115538 (2017
-11-03
)
Page 5 of 206
Printed on : 2017-11-03
