Use In Special Populations; Pregnancy; Use Of Multiple Stents; Drug Information - Boston Scientific SYNERGY Mode D'emploi

narrow therapeutic index. Everolimus has also been shown to reduce the clearance of some
prescription medications when it was administered orally along with cyclosporine (CsA).
Everolimus, when prescribed as an oral medication, may interact with the following drugs
or substances.
note: The list below describes interactions for orally administrated everolimus at
significantly higher doses than are present on the SYNERGY™ Stent System. Interactions
observed at these higher, oral doses may not be relevant to the SYNERGY Stent System.
• CYP3A4 isozyme inhibitors (ketoconazole, itraconazole, ritonavir, erythromycin,
clarithromycin, fluconazole, calcium channel blockers)
• Inducers of CYP3A4 isozyme (rifampicin, rifabutin, carbamazepin, phenobarbital, phenytoin)
• Antibiotics (Ciprofloxacin, ofloxacin)
• Glucocorticoids
• HMGCoA reductase inhibitors (simvastatin, lovastatin)
• Digoxin
• Cisapride (theoretical potential interaction)
• Sildenafil (Viagra™) (theoretical potential interaction)
• Antihistaminics (terfenadine, astemizole)
• Grapefruit juice
Because systemic everolimus levels are below the lower limit of detection in pre-clinical
studies after two days, formal drug interaction studies have not been performed with
SYNERGY Stent System. 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 SYNERGY
stent in a subject taking a drug with known interaction with everolimus.

Use in special populations:

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. While there is no contraindication, the
risks and reproductive effects are unknown. It is not recommended that the SYNERGY Stent
System be used in women attempting to conceive, or who are pregnant.

Use of Multiple stents

Potential interactions of the SYNERGY stent with other drug-eluting or coated stents have not
been evaluated in vivo. Patients should be treated with no more than 2 planned SYNERGY stents.
Additional stents may be placed if bailout stenting is required. The use of multiple drug-eluting
stents will expose the patient to larger amounts of drug and polymer.
When more than one stent is required and results in stent-to-stent contact, stent materials should
be of similar composition to avoid the possibility of corrosion due to the presence of dissimilar
metals in a conducting medium. Placing multiple stents of different metals in contact with each
other may increase the potential for corrosion, though in vitro tests to assess stent-to-stent
contact using a platinum chromium alloy stent in combination with a 316L stainless steel or
cobalt-chromium alloy stent suggest there is no increased risk of corrosion with this pair. If more
than one SYNERGY stent is needed to cover the lesion, it is suggested that, to avoid the potential
for gap restenosis, the stents be adequately overlapped (with a minimum of 2 mm overlap).

Drug Information:

Mechanism of action

The mechanism by which the SYNERGY stent inhibits neointimal growth has not been
established. At the cellular level, everolimus inhibits growth factor-stimulated cell proliferation.
At the molecular level, everolimus forms a complex with the cytoplasmic protein FKBP-12
(FK 506 Binding Protein). This complex binds to and interferes with FRAP (FKBP-12 Rapamycin
Associated Protein), also known as mTOR (mammalian Target of Rapamycin), leading to
inhibition of cell metabolism, growth and proliferation by arresting the cell cycle at the late
G1 stage.

Drug Interactions

See precautions, Drug Interactions.

carcinogenicity, Genotoxicity, and reproductive toxicology

Carcinogenicity, genotoxicity, and reproductive toxicology of SYNERGY stent were not
evaluated. However, testing has been completed on PROMUS (Xience V™). PROMUS
(Xience V) and SYNERGY use the same drug (everolimus) and release profile. A 26-week
carcinogenicity study was conducted to evaluate the carcinogenic potential of PROMUS
(Xience V) everolimus-eluting stents following subcutaneous implantation in transgenic mice.
During the course of the study, there were no abnormal clinical observations that suggested a
carcinogenic effect of the test group PROMUS (Xience V). The test group did not demonstrate
an increased incidence of neoplastic lesions when compared to the negative control group.
However, the positive control and the experimental positive control groups demonstrated
notable increases in the incidence of neoplastic lesions compared to either the test or the
negative control group. Based on the results of this study, the PROMUS (Xience V) stent does
not appear to be carcinogenic when implanted in transgenic mice for 26 weeks.
In addition, a reproductive toxicity (teratology) study was conducted to demonstrate that
implantation of PROMUS (Xience V) stents in female Sprague-Dawley rats does not affect their
fertility or reproductive capability and shows a lack of any reproductive toxicity on their offspring.
The PROMUS (Xience V) stent did not affect the fertility or reproductive capability of female
Sprague-Dawley rats. There was no statistical difference between the test article PROMUS
(Xience V) stent and the control system in terms of any of the evaluated parameters. The test
article had no effect on litter size and caused no increase of in utero mortality. Additionally, the
PROMUS (Xience V) stent did not cause any reproductive toxicity in the offspring in this study.

aDverse events

Potential adverse events (in alphabetical order) which may be associated with the
implantation of a coronary stent in a native coronary artery include those risks associated
with percutaneous transluminal coronary angioplasty as well as additional risks related to the
use of the stent as listed below.
• Abrupt stent closure
• Acute myocardial infarction
• Allergic reaction to anti-coagulant and/or antiplatelet therapy, contrast medium, or stent
materials
• Angina
• Arrhythmias, including ventricular fibrillation and ventricular tachycardia
• Arteriovenous fistula
• Bleeding
• Cardiac tamponade
• Cardiogenic shock/pulmonary edema
• Coronary aneurysm
• Death
• Dissection
• Emboli, distal (air, tissue, or thrombotic material or material from device(s) used in the
procedure)
• Heart failure
• Hematoma
• Hemorrhage, which may require transfusion
• Hypotension/hypertension
• Infection, local or systemic
• Ischemia, myocardial
• Pain, access site
• Perforation or rupture of coronary artery
• Pericardial effusion
• Pseudoaneurysm, femoral
• Renal insufficiency or failure
• Respiratory failure
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