corm
`
`10056733-3
`
`Instructions for Use
`CYPHER™ Sirolimus-eluting Coronary Stent on RAPTORTM
`Over-the-Wire Delivery System
`
`and
`
`CYPHER™ Sirolimus-eluting Coronary Stent on RAPTORRAIL®
`Rapid Exchange Delivery System
`
`1
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`Page 1
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`Medtronic Exhibit 1422
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`

`

`Table of Contents
`
`Product Description .................................................................................................................................................................................. 3
`1.1. Device Component Description ........................................................................................................................................................ 3
`Table 1-1: Device Component Description ...................................................................................................................................... 3
`1.2. Drug Component Description ........................................................................................................................................................... 3
`Table 1-2: CYPHERTM Sirolimus-eluting Coronary Stent System Product Matrix & Nominal Sirolimus Dosages ........................... 4
`Indications ................................................................................................................................................................................................. 4
`Contraindications ...................................................................................................................................................................................... 4
`Warnings .................................................................................................................................................................................................... 4
`Precautions ............................................................................................................................................................................................... 4
`5.1. General Precautions ........................................................................................................................................................................ 4
`5.2. Use of Multiple Stents ...................................................................................................................................................................... 4
`5.3. Brachytherapy .................................................................................................................................................................................. 4
`5.4. Use in Conjunction with Other Procedures ...................................................................................................................................... 5
`5.5. Use in Special Populations .............................................................................................................................................................. 5
`5.6.
`Lesion/Vessel Characteristics .......................................................................................................................................................... 5
`5.7. Drug Interactions .............................................................................................................................................................................. 5
`5.8. Coronary Artery Surgery – Effect on Anastomoses ......................................................................................................................... 5
`5.9.
`Immune Suppression Potential ........................................................................................................................................................ 5
`5.10. Lipid Elevation Potential ................................................................................................................................................................... 5
`5.11. Magnetic Resonance Imaging (MRI) – Stent Migration ................................................................................................................... 5
`5.12. Stent Handling Precautions .............................................................................................................................................................. 5
`5.13. Stent Placement Precautions ........................................................................................................................................................... 5
`5.14. Stent/System Removal Precautions ................................................................................................................................................ 6
`5.15. Post Implantation Precautions ........................................................................................................................................................ 6
`Drug Information ...................................................................................................................................................................................... 6
`6.1. Mechanism of Action ....................................................................................................................................................................... 6
`6.2. Pharmacokinetics of the CYPHER Sirolimus-eluting Coronary Stent ............................................................................................. 6
`Table 6-1: Whole Sirolimus Pharmacokinetic Parameters in Patients after Implantation of CYPHER Sirolimus-eluting Coronary Stents ........ 6
`6.3. Pharmacokinetics Following Oral Administration of Sirolimus ........................................................................................................ 6
`Table 6-2: Pharmacokinetic Parameters in Healthy Subjects, Renal Transplant Patients and Patients with Hepatic Impairment
`Following Oral Administration of Sirolimus ....................................................................................................................................... 7
`6.4. Drug Interactions Following Oral Administration of Sirolimus .......................................................................................................... 7
`6.5. Mutagenesis, Carcinogenicity and Reproductive Toxicology ........................................................................................................... 8
`6.6. Pregnancy ........................................................................................................................................................................................ 8
`6.7.
`Lactation ........................................................................................................................................................................................... 8
`Adverse Events ........................................................................................................................................................................................ 9
`7.1. Observed Adverse Events .............................................................................................................................................................. 9
`Table 7-1: Clinical Studies - Major Characteristics .......................................................................................................................... 9
`Table 7-2: Principal Adverse Events Observed in Clinical Studies In-Hospital and Out-of-Hospital .............................................. 10
`Table 7-3: Frequency of Incomplete Stent Apposition ................................................................................................................... 10
`7.2. Potential Adverse Events ............................................................................................................................................................... 11
`Clinical Studies ....................................................................................................................................................................................... 11
`8.1. Overview of Clinical Studies ........................................................................................................................................................... 11
`Table 8-1: Clinical Study Comparison ............................................................................................................................................ 11
`8.2. SIRIUS Trial (Pivotal Study) ........................................................................................................................................................... 12
`Table 8-2: Principal Effectiveness and Safety Results (to 360 Days) ............................................................................................ 13
`Figure 8-1: Kaplan-Meier Graph and Life Table to 360 Days ........................................................................................................ 14
`8.3. RAVEL Trial
`.................................................................................................................................................................................. 14
`Table 8-3: Principal Effectiveness and Safety Results (to 720 Days) ............................................................................................ 15
`Figure 8-2: Kaplan-Meier Graph and Life Table to 720 Days ........................................................................................................ 16
`First-in-Man Study .......................................................................................................................................................................... 17
`Table 8-4: First-in-Man: Effectiveness and Safety Results ............................................................................................................ 17
`Individualization of Treatment ............................................................................................................................................................... 17
`Patient Counseling Information ............................................................................................................................................................. 17
`How Supplied .......................................................................................................................................................................................... 17
`Operator’s Manual (Combined OTW and RX) ....................................................................................................................................... 18
`12.1. Access to Package Holding Sterile Stent Delivery System ............................................................................................................ 18
`12.2.
`Inspection Prior to Use ................................................................................................................................................................... 18
`12.3. Materials Required ......................................................................................................................................................................... 18
`12.4. Preparation .................................................................................................................................................................................. 18
`12.5. Delivery Procedure ......................................................................................................................................................................... 18
`12.6. Deployment Procedure ................................................................................................................................................................... 18
`12.7. Further Dilatation of Stented Segments ......................................................................................................................................... 19
`12.8. Removal Procedure ........................................................................................................................................................................ 19
`12.9. In-Vitro Information ......................................................................................................................................................................... 19
`Table 12-1: Inflation Pressure Recommendations ......................................................................................................................... 19
`Patient Information ................................................................................................................................................................................. 19
`Patents ..................................................................................................................................................................................................... 19
`Disclaimer of Warranty and Limitation of Remedy .............................................................................................................................. 19
`
`8.4.
`
`1.
`
`2.
`3.
`4.
`5.
`
`6.
`
`7.
`
`8.
`
`9.
`10.
`11.
`12.
`
`13.
`14.
`15.
`
`2
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`Page 2
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`Medtronic Exhibit 1422
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`

`

`Caution: Federal (USA) law restricts this device to sale by or on the order of a physician.
`
`1.
`
`Product Description
`The CYPHER™ Sirolimus-eluting Coronary Stent (CYPHER Stent) is a combination product comprised of two regulated components: a
`device (a stent system) and a drug product (a formulation of sirolimus in a polymer coating).
`
`1.1.
`
`Device Component Description
`The device component consists of a stent mounted onto a stent delivery system (SDS). The physical characteristics of the device
`component are shown in Table 1-1.
`
`Table 1-1: Device Component Description
`
`CYPHERTM Sirolimus-eluting Coronary Stent
`on RAPTORTM Over-the-Wire (OTW) Stent
`Delivery System
`
`CYPHERTM Sirolimus-eluting Coronary Stent
`on RAPTORRAIL® Rapid Exchange (RX)
`Stent Delivery System
`
`8, 13, 18, 23, 28, 33
`
`8, 13, 18, 23, 28, 33
`
`2.50, 2.75, 3.00, 3.50
`2.50, 2.75, 3.00, 3.50
`Electropolished stainless steel (316L), laser-cut from seamless tubing in a sinusoidal pattern coated
`with a polymer and sirolimus mixture.
`Six circumferential cells (2.50 – 3.00 mm stents) or
`Seven circumferential cells (3.50 mm stents)
`< 1 mm
`137 cm
`145 cm
`Single access port to the inflation lumen.
`Y-Connector (Side arm for access to balloon
`A guidewire exit port is located at 28 cm
` inflation/deflation lumen. Straight arm is
`from the tip. Designed for guidewire
`continuous with shaft inner lumen – designed
`< 0.014" (0.36 mm).
`for guidewire < 0.014" (0.36 mm).)
`Single-layer nylon, nominally 2 mm longer than stent. Mounted stent length and location is defined
`by 2 platinum-iridium radiopaque marker bands.
`Nominal pressure: 11 atm (1115 kPa)
`Rated burst pressure: 16 atm (1621 kPa)
`
`Available Stent Lengths,
`unexpanded (mm):
`Available Stent Diameters (mm):
`Stent Material:
`
`Stent Geometry:
`
`Nominal Stent Foreshortening:
`Delivery System Usable Length:
`Delivery System Y-Adapter Ports:
`
`Stent Delivery Balloon:
`
`Balloon Inflation Pressure:
`
`Guiding Catheter Inner Diameter:
`
`> 0.067" (1.7 mm)
`
`Catheter Shaft Outer Diameter:
`
`3.3F (1.10 mm) proximally,
`2.7F (0.90 mm) distally.
`
`> 0.056" (1.4 mm) for 2.50 – 3.00 mm
`> 0.067" (1.7 mm) for 3.50 mm
`
`2.3F (0.75 mm) proximally; 2.6F (0.85 mm) distally
`(Ø up to 3.00 mm); 2.9F (0.95 mm) distally (Ø >
`3.00 mm).
`
`1.2.
`
`Drug Component Description
`The active ingredient in the CYPHER Sirolimus-eluting Coronary Stent is sirolimus (also known as rapamycin). Sirolimus is a
`macrocyclic lactone produced by Streptomyces hygroscopicus. The chemical name of sirolimus (also known as rapamycin) is
`(3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-
`hexadecahydro-9,27-dihydroxy-3-[(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-1-methylethyl]-10,21-dimethoxy-
`6,8,12,14,20,26-hexamethyl-23,27-epoxy-3H-pyrido[2,1-c ][1,4] oxaazacyclohentriacontine-1,5,11,28,29 (4H,6H,31H)-pentone. Its
`molecular formula is C51H79NO13 and its molecular weight is 914.2. The structural formula of sirolimus is shown below:
`
`Sirolimus is a white to off-white powder and is insoluble in water, but freely soluble in benzyl alcohol, chloroform, acetone, and
`acetonitrile. Please refer to Table 1-2 for the nominal dosages of sirolimus on the CYPHER Sirolimus-eluting Coronary Stents.
`
`3
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`The inactive ingredients in the CYPHER Sirolimus-eluting Coronary Stent contain parylene C and the following two non-erodible
`polymers: polyethylene-co-vinyl acetate (PEVA) and poly n-butyl methacrylate (PBMA). A combination of the two polymers mixed
`with sirolimus (67%/33%) makes up the basecoat formulation which is applied to a parylene C treated stent. A drug-free topcoat of
`PBMA polymer is applied to the stent surface to control the release kinetics of sirolimus. The drug/polymer coating is adhered to the
`entire surface (i.e., luminal and abluminal) of the stent. The structural formulae of the polymer subunits are shown below:
`
` PEVA
`
` PBMA Parylene C
`
`Table 1-2: CYPHER Sirolimus-eluting Coronary Stent System
`Product Matrix & Nominal Sirolimus Dosages
`
`Product Code
`
`OTW
`
`RX
`
`Nominal
`Expanded
`Stent ID
`(mm)
`
`Nominal
`Unexpanded
`Stent Length
`(mm)
`
`Nominal
`Sirolimus
`Content
`(µg)
`
`Product Code
`
`OTW
`
`RX
`
`Nominal
`Expanded
`Stent ID
`(mm)
`
`Nominal
`Unexpanded
`Stent Length
`(mm)
`
`Nominal
`Sirolimus
`Content
`(µg)
`
`CWS08250 CXS08250
`CWS08275 CXS08275
`CWS08300 CXS08300
`CWS08350 CXS08350
`CWS13250 CXS13250
`CWS13275 CXS13275
`CWS13300 CXS13300
`CWS13350 CXS13350
`CWS18250 CXS18250
`CWS18275 CXS18275
`CWS18300 CXS18300
`CWS18350 CXS18350
`
`2.50
`2.75
`3.00
`3.50
`2.50
`2.75
`3.00
`3.50
`2.50
`2.75
`3.00
`3.50
`
` 8
` 8
` 8
` 8
`13
`13
`13
`13
`18
`18
`18
`18
`
`71
`71
`71
`83
`111
`111
`111
`129
`150
`150
`150
`175
`
`CWS23250
`CWS23275
`CWS23300
`CWS23350
`CWS28250
`CWS28275
`CWS28300
`CWS28350
`CWS33250
`CWS33275
`CWS33300
`CWS33350
`
`CXS23250
`CXS23275
`CXS23300
`CXS23350
`CXS28250
`CXS28275
`CXS28300
`CXS28350
`CXS33250
`CXS33275
`CXS33300
`CXS33350
`
`2.50
`2.75
`3.00
`3.50
`2.50
`2.75
`3.00
`3.50
`2.50
`2.75
`3.00
`3.50
`
`23
`23
`23
`23
`28
`28
`28
`28
`33
`33
`33
`33
`
`190
`190
`190
`221
`229
`229
`229
`268
`268
`268
`268
`314
`
`2.
`
`Indications
`The CYPHER Sirolimus-eluting Coronary Stent is indicated for improving coronary luminal diameter in patients with symptomatic ischemic
`disease due to discrete de novo lesions of length < 30 mm in native coronary arteries with a reference vessel diameter of > 2.5 to < 3.5 mm.
`
`Long-term outcome (beyond 12 months) for this permanent implant is unknown at present.
`
`3. Contraindications
`Use of the CYPHER Sirolimus-eluting Coronary Stent is contraindicated in the following patient types:
`•
`Patients with a hypersensitivity to sirolimus or its derivatives.
`•
`Patients with a known hypersensitivity to polymethacrylates or polyolefin copolymers.
`
`Coronary artery stenting is contraindicated for use in:
`•
`Patients in whom antiplatelet and/or anticoagulation therapy is contraindicated.
`•
`Patients judged to have a lesion that prevents complete inflation of an angioplasty balloon.
`
`4. Warnings
`•
`Please ensure that the inner package has not been opened or damaged as this may indicate the sterile barrier has been breached.
`•
`The use of this device carries the risks associated with coronary artery stenting, including subacute thrombosis, vascular
`complications, and/or bleeding events.
`Patients with a known hypersensitivity to 316L stainless steel may suffer an allergic reaction to this implant.
`
`•
`
`Precautions
`5.1.
`General Precautions
`•
`Only physicians who have received adequate training should perform implantation of the stent.
`•
`Stent placement should only be performed at hospitals where emergency coronary artery bypass graft surgery can be
`readily performed.
`Subsequent stent blockage may require repeat dilatation of the arterial segment containing the stent. The long-term
`outcome following repeat dilatation of endothelialized stents is not well characterized.
`To avoid the possibility of dissimilar metal corrosion, do not implant stents of different materials in tandem where overlap or
`contact is possible.
`Do not use Ethiodol or Lipiodol contrast media.1
`Do not expose the delivery system to organic solvents, such as alcohol, or detergents.
`
`•
`
`•
`
`•
`•
`
`5.2.
`
`5.3.
`
`Use of Multiple Stents
`The extent of the patient’s exposure to drug and polymer is directly related to the number of stents implanted. Use of more than two
`CYPHER Stents has not received adequate clinical evaluation. Use of more than two CYPHER Stents will result in the patient
`receiving larger amounts of drug and polymer than the experience reflected in the clinical studies.
`
`Brachytherapy
`The safety and effectiveness of the CYPHER Stent in patients with prior brachytherapy of the target lesion have not been
`established. The safety and effectiveness of use of brachytherapy to treat in-stent restenosis in a CYPHER Stent have not been
`established. Both vascular brachytherapy and the CYPHER Stent alter arterial remodeling. The synergy between these two
`treatments has not been determined.
`
`Ethiodol and Lipiodol are trademarks of Guerbet, S.A.
`
`5.
`
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`5.4.
`
`5.5.
`
`5.6.
`
`5.7.
`
`5.8.
`
`5.9.
`
`Use in Conjunction with Other Procedures
`The safety and effectiveness of using mechanical atherectomy devices (directional atherectomy catheters, rotational atherectomy
`catheters) or laser angioplasty catheters in conjunction with CYPHER Stent implantation have not been established.
`
`Use in Special Populations
`5.5.1.
`Pregnancy: Pregnancy Category C. See Drug Information – 6.6 Pregnancy.
`There are no adequate and well controlled studies in pregnant women. Effective contraception should be initiated before
`implanting a CYPHER Stent and for 12 weeks after implantation. The CYPHER Stent should be used during pregnancy
`only if the potential benefit outweighs the potential risk to the embryo or fetus.
`Use during lactation: See Drug Information – 6.7 Lactation. A decision should be made whether to discontinue
`nursing or to implant the stent, taking into account the importance of the stent to the mother.
`Pediatric use: The safety and efficacy of the CYPHER Stent in pediatric patients below the age of 18 years have not
`been established.
`Geriatric use: Clinical studies of the CYPHER Stent did not find that patients age 65 years and over differed with
`regard to safety and efficacy compared to younger patients.
`
`5.5.2.
`
`5.5.3.
`
`5.5.4.
`
`Lesion/Vessel Characteristics
`The safety and effectiveness of the CYPHER Stent have not been established in the following patient populations:
`•
`Patients with unresolved vessel thrombus at the lesion site.
`•
`Patients with coronary artery reference vessel diameter < 2.5 mm or > 3.5 mm.
`•
`Patients with lesions located in the left main coronary artery, ostial lesions, or lesions located at a bifurcation.
`•
`Patients with diffuse disease or poor overflow distal to the identified lesions.
`•
`Patients with tortuous vessels in the region of the obstruction or proximal to the lesion.
`•
`Patients with a recent acute myocardial infarction where there is evidence of thrombus or poor flow.
`
`Drug Interactions
`Several drugs are known to affect the metabolism of sirolimus, and other drug interactions may be inferred from known metabolic
`effects. Sirolimus is known to be a substrate for both cytochrome P450 IIIA4 (CYP3A4) and P-glycoprotein. See Drug Information –
`6.4 Drug Interactions Following Oral Administration of Sirolimus for more specific information.
`
`Consideration should be given to the potential for drug interaction when deciding to place a CYPHER Stent in a patient who is taking
`a drug that could interact with sirolimus, or when deciding to initiate therapy with such a drug in a patient who had recently received a
`CYPHER Stent. The effect of drug interactions on the safety or efficacy of the CYPHER Stent has not been determined.
`
`Coronary Artery Surgery – Effect on Anastomoses
`There have been rare reports of bronchial anastomotic dehiscence of transplant anastomoses in lung transplant patients who were
`receiving oral sirolimus therapy. In a vessel that has recently been implanted with a CYPHER Stent, the sirolimus concentrations are
`expected to be several fold higher than systemic sirolimus concentrations. Therefore, consideration should be given to the possibility
`that the presence of a CYPHER Stent may compromise the healing of coronary artery vascular anastomoses. No such event was
`observed in the very limited experience from clinical trials.
`
`Immune Suppression Potential
`Sirolimus, the active ingredient of the CYPHER Stent, is an immunosuppressive agent that is also available in oral formulations. The
`mean peak systemic blood concentration of sirolimus following placement of up to two CYPHER Stents (1.05 ng/ml) is substantially
`lower than the therapeutic concentrations usually obtained when sirolimus oral formulations are used as prophylaxis for renal
`transplant rejection (see Drug Information – Pharmacokinetics (6.2)). In clinical studies of CYPHER Stents when used according
`to its intended use, there were no reports of immune suppression. However, for patients who receive several CYPHER
`Stents simultaneously, it may be possible for systemic concentrations of sirolimus to approach immunosuppressive levels
`temporarily, especially in patients who also have hepatic insufficiently or who are taking drugs that inhibit CYP3A4 or P-glycoprotein.
`This possibility should be considered for such patients, particularly if they are also taking oral sirolimus (or rapamycin), other
`immunosuppressive agents, or are otherwise at risk for immune suppression.
`
`5.10.
`
`Lipid Elevation Potential
`The use of oral sirolimus in renal transplant patients was associated with increased serum cholesterol and triglycerides that 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, the systemic sirolimus concentrations from the CYPHER Stent are expected to be lower
`than the concentrations usually obtained in transplant patients, but the magnitude and duration of any effect of those concentrations
`on lipids is not known.
`
`5.11. Magnetic Resonance Imaging (MRI) – Stent Migration
`An MRI scan should not be performed on a patient after stent implantation until there is adequate neointimal investment of the stent
`because of a potential for stent migration. For a conventional uncoated 316L stainless steel stent this period is usually considered to
`be eight weeks. Because of the reduced neointimal formation associated with the CYPHER Stent, the period of vulnerability may be
`longer, but there is currently insufficient information to provide a specific recommendation.
`
`5.12.
`
`5.13.
`
`•
`•
`
`Stent Handling Precautions
`For single use only. Do not resterilize or reuse this device. Note the “Use By” date on the product label.
`•
`Do not remove the stent from the delivery balloon – removal may damage the stent and/or lead to stent
`•
`embolization. The stent system is intended to perform as a system.
`Do not induce a vacuum on the delivery system prior to reaching the target lesion.
`Special care must be taken not to handle or in any way disrupt the stent on the balloon. This is most important while
`removing the catheter from the packaging, placing it over the guidewire, and advancing it through the large-bore rotating
`hemostatic valve and guiding catheter hub.
`Stent manipulation (e.g., rolling the mounted stent with your fingers) may loosen the stent from the delivery system balloon
`and cause dislodgment.
`Use only the appropriate balloon inflation media. Do not use air or any gaseous medium to inflate the balloon as this may
`cause uneven expansion and difficulty in deployment of the stent.
`
`•
`
`•
`
`•
`
`Stent Placement Precautions
`Do not prepare or pre-inflate the balloon prior to stent deployment other than as directed. Use the balloon purging
`•
`technique described in Section 12 – Operator's Manual.
`Guiding catheters used must have lumen sizes that are suitable to accommodate the stent delivery system (see Product
`Description – 1.1 Device Component Description).
`Do not induce a negative pressure on the delivery catheter prior to placement of the stent across the lesion. This may
`cause premature dislodgment of the stent from the balloon.
`Although the stent delivery balloon catheter is strong enough to expand the stent without rupture, a circumferential tear of
`the carrier balloon distal to the stent and prior to complete expansion of the stent could cause the balloon to become
`tethered to the stent, requiring surgical removal. In case of rupture of the balloon, it should be withdrawn and, if necessary,
`a new balloon catheter exchanged over the guidewire to complete the expansion of the stent.
`
`•
`
`•
`
`5
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`

`•
`
`•
`
`•
`•
`
`•
`
`•
`
`•
`
`Implanting a stent may lead to a dissection of the vessel distal and/or proximal to the stented portion and may cause acute
`closure of the vessel requiring additional intervention (CABG, further dilatation, placement of additional stents, or other
`intervention).
`Do not expand the stent if it is not properly positioned in the vessel. (See Precautions – 5.14 Stent/System Removal
`Precautions.)
`Placement of the stent has the potential to compromise side branch patency.
`Balloon pressures should be monitored during inflation. Do not exceed rated burst pressure as indicated on the
`product label. (See Inflation Pressure Recommendations in Table 12-1.) Use of pressures higher than those specified
`on the product label may result in a ruptured balloon with possible intimal damage and dissection.
`Do not attempt to pull an unexpanded stent back through the guiding catheter, as dislodgment of the stent from
`the balloon may occur. Remove as a single unit per instructions in Precautions – 5.14 Stent/System Removal
`Precautions.
`Stent retrieval methods (use of additional wires, snares and/or forceps) may result in additional trauma to the coronary
`vasculature and/or the vascular access site. Complications may include bleeding, hematoma, or pseudoaneurysm.
`Ensure full coverage of the entire lesion/dissection site so that there are no gaps between stents.
`
`5.14.
`
`Stent/System Removal Precautions
`Should unusual resistance be felt at any time during either lesion access or removal of the stent delivery system before stent
`implantation, the entire system should be removed as a single unit.
`
`When removing the delivery system as a single unit:
`•
`Do not retract the delivery system into the guiding catheter.
`•
`Advance the guidewire into the coronary anatomy as far distally as safely possible.
`•
`Tighten the rotating hemostatic valve to secure the stent delivery system to the guiding catheter; then remove the guiding
`catheter and stent delivery system as a single unit.
`
`Failure to follow these steps or applying excessive force to the stent delivery system can potentially result in loss or damage to the
`stent or stent delivery system.
`
`If it is necessary to retain the guidewire in position for subsequent artery/lesion access, leave the guidewire in place and remove all
`other system components.
`
`5.15.
`
`Post Implantation Precautions
`Great care must be exercised when crossing a newly deployed stent with an intravascular ultrasound (IVUS) catheter, a
`•
`coronary guidewire or balloon catheter to avoid disrupting the stent geometry.
`Do not perform a magnetic resonance imaging (MRI) scan on a patient after stent implantation until there is adequate
`neointimal investment of the stent (see Precautions – 5.11 Magnetic Resonance Imaging (MRI) – Stent Migration). The
`stent may cause artifacts in MRI scans due to distortion of the magnetic field.
`
`•
`
`6. Drug Information
`6.1.
`Mechanism of Action
`The mechanism (or mechanisms) by which a CYPHER Stent affects neointima production as seen in clinical studies has not been
`established. It is known that sirolimus inhibits T-lymphocyte activation and smooth muscle and endothelial cell proliferation in
`response to cytokine and growth factor stimulation. In cells, sirolimus binds to the immunophilin, FK Binding Protein-12 (FKBP-12).
`The sirolimus-FKBP-12 complex binds to and inhibits the activation of the mammalian Target of Rapamycin (mTOR), leading to
`inhibition of cell cycle progression from the G1 to the S phase.
`
`6.2.
`
`Pharmacokinetics of the CYPHER Sirolimus-eluting Coronary Stent
`The pharmacokinetics of sirolimus as delivered by the CYPHER Sirolimus-eluting Coronary Stent has been determined in patients
`with coronary artery disease after implantation