Indications, safety and warnings for Ranger™ Drug Coated Balloon

The Ranger DCB is indicated for percutaneous transluminal angioplasty (PTA) of de novo or restenotic lesions up to 180 mm in length located in native superficial femoral and proximal popliteal arteries (SFA / PPA), with reference vessel diameters of 4 mm to 7 mm.

Use of the Ranger DCB is contraindicated in:

• Patients with known hypersensitivity to paclitaxel (or structurally-related compounds).
• Patients who cannot receive recommended antiplatelet and/or anticoagulation therapy.
• Women who are breastfeeding, pregnant or men intending to father children.
• Patients judged to have a lesion that prevents complete inflation of an angioplasty balloon or proper placement of the delivery system.
• Coronary arteries, renal arteries, and supra-aortic/cerebrovascular arteries.

• Never use air or any gaseous medium to inflate the balloon (a 50:50 mixture of contrast medium and sterile saline is recommended).
• Do not advance or retract the catheter unless the balloon is fully deflated under vacuum.
• If unusual resistance is felt during manipulation, determine the cause of the resistance before proceeding. If the source of resistance cannot be determined, it is recommended to extract the entire system with the guiding sheath.
• If difficulty is experienced during balloon inflation, do not continue. Deflate the balloon and remove the catheter.
• To reduce the potential for vessel trauma, the inflated diameter of the balloon should approximate the diameter of the vessel segment to be treated. The inflated length of the balloon (shoulder to shoulder) may exceed the length of the lesion / stenosis by approximately 10 mm on either side within the targeted artery.
• Do not exceed the balloon rated burst pressure. Use of an inflation device is recommended to prevent over-pressurization.
• The safety of using multiple Ranger DCBs with a total drug dosage exceeding 9266 μg of paclitaxel in a patient has not been studied.
• Using a drug-eluting stent in conjunction with Ranger DCB at the same treatment site has not been studied

Pre- and Post-Procedure Antiplatelet Therapy
It is strongly advised that the treating physician follow the Inter-Society Consensus (TASC II) Guidelines recommendations (or other applicable country guidelines) for antiplatelet therapy pre- and post-procedure.

• The balloon catheter should be used with caution for procedures involving calcified lesions due to the abrasive nature of these lesions.
• The balloon catheter is not intended for injection of contrast medium.
• Full arterial wall apposition of the Ranger DCB is necessary for proper drug transfer to the vessel.
• If unusual resistance is felt during positioning of the loading tool, do not use the balloon catheter. Replace with a new Ranger DCB.
• If unusual resistance is felt during catheter advancement through the valve, do not use the balloon catheter. Replace with a new Ranger DCB.
• Do not touch, wipe, bend, or squeeze the balloon. Do not allow it to contact any liquids including organic solvents such as alcohol or detergents prior to insertion. Damage to the balloon coating or premature release of the drug may occur.
• To minimize the possible introduction of air into the system, it is imperative that prior to proceeding, careful attention is paid to the maintenance of tight catheter connections and thorough aspiration and flushing of the system.
• If using a Tuohy-Borst type adapter, take care not to over-tighten the hemostatic valve around the catheter shaft as lumen constriction may occur, affecting inflation / deflation of the balloon or damaging the drug coating.
• Never advance the balloon catheter without the guidewire extending from the distal tip.
• When using a sheath, do not insert the loading tool more than 20 mm into the sheath valve.
• This product should not be used in patients with uncorrected bleeding disorders or patients who cannot receive anticoagulation or antiplatelet aggregation therapy.
• If loading tool tip will not enter the guide / introducer sheath valve, forcing the loading tool can cause catheter shaft kinking and damage to drug coating when advancing the catheter. Consider replacing introducer sheath.
• If treating a long lesion (longer than the maximum balloon length available), each individual segment should be treated only once with a drug-coated balloon. Treat each segment with a new balloon, and try to minimize overlapping of treated segments.

Pregnancy / Lactation
This product has not been tested in pregnant or breastfeeding women or in men intending to father children; effects on the developing fetus have not been studied and the risks and reproductive effects remain unknown. It is not recommended that the Ranger DCB be used in women attempting to conceive, or who are pregnant. Prior to use, careful consideration should be given to the continuation of breastfeeding, taking into account the importance of the procedure to the mother. It is not known whether paclitaxel is distributed in human milk. In lactating rats, milk concentrations appeared to be higher than maternal plasma levels and declined in parallel with the maternal levels. Mothers should be advised of the potential for serious adverse reactions to paclitaxel in nursing infants.

Drug Information
The mechanism of action by which paclitaxel reduces or reverses neointima formation and proliferation, leading to restenosis, as demonstrated in clinical studies has not been established. It is known that paclitaxel promotes the assembly of microtubules from tubulin dimers and stabilizes microtubules by preventing depolymerization. This stability results in the inhibition of the normal dynamic reorganization of the microtubule network that is essential for vital interphase and mitotic cellular functions.

Drug Interaction
Possible interactions of paclitaxel with concomitantly administered medications have not been formally investigated. Drug interactions of systemic hemotherapeutic levels of paclitaxel with possible concomitant medications are outlined in the labeling for finished pharmaceuticals containing paclitaxel, such as TAXOL.

Carcinogenicity, Genotoxicity, and Reproductive Toxicology
No long-term studies in animals have been published in peer reviewed literature to evaluate the carcinogenic potential of paclitaxel. Paclitaxel interacts with microtubules; this is the major mechanism by which it inhibits cell growth. One consequence is the loss of whole chromosomes via interactions with spindle microtubules during cell division. As such, paclitaxel is defined as an aneugen (agent causing an alteration in chromosome number). This indirect action is consistent with positive responses in in vitro and in vivo micronucleus genotoxicity assays, which detect DNA fragments. Positive results have also been reported for chromosomal aberrations in primary human lymphocytes. It is not known whether paclitaxel has a separate direct action on DNA in the generation of DNA strand breaks or fragments. It is negative in assays for gene mutation, including salmonella and CHO/HPRT. Paclitaxel administered via IV prior to and during mating produced impairment of fertility in male and female rats at doses > 1 mg/kg. Administration of paclitaxel during the period of organogenesis to rabbits at doses of 3 mg/kg/day caused embryo- and fetotoxicity. Maternal toxicity was also observed at this dose. No teratogenic effects were observed at 1 mg/kg/day; teratogenic potential could not be assessed at higher doses due to extensive fetal mortality. For comparison, the worst-case dose of paclitaxel delivered by the Ranger DCB (assuming maximum size and number of balloons used in a lesion) is  9266 μg, which is approximately 6 and 19 times less than the dose that saw effects in rats and rabbits, respectively, when normalizing to body weight. 

Potential adverse events which may be associated with the use of Ranger Drug-Coated Balloon include, but are not limited to, the following:

• Allergic reaction (device, contrast, other)
• Death
• Embolism (air, plaque, thrombus, device, tissue, or other)
• Hematoma
• Hemorrhage / Bleeding
• Hypotension / Hypertension
• Infection / Sepsis
• Restenosis of treated vessel
• Thrombus / Thrombosis
• Vasospasm
• Vessel occlusion
• Vessel trauma (e.g., Arteriovenous fistula, dissection, perforation, pseudoaneurysm, rupture)

Potential adverse events not captured above that may be unique to the paclitaxel drug coating:

• Allergic / immunologic reaction to drug (paclitaxel or structurally-related compounds) or coating or its individual components
• Alopecia
• Anemia
• Blood product transfusion
• Gastrointestinal symptoms
• Hematologic dyscrasia (including leukopenia, neutropenia, thrombocytopenia)
• Hepatic enzyme changes
• Histologic changes in vessel wall, including inflammation, cellular damage or necrosis
• Myalgia / Arthralgia
• Peripheral neuropathy

Apart from hypersensitivity reactions (allergic / immunologic reactions), the likelihood of paclitaxel related adverse events is low due to the low exposure. There may be other potential adverse events that are unforeseen at this time.

User Information: Only physicians who are familiar with the principles, clinical applications, complications, side effects, and hazards commonly associated with native superficial femoral or popliteal artery interventional procedures should use this device.

The Ranger Drug-Coated Balloon (DCB) catheter is indicated for percutaneous transluminal angioplasty (PTA) of de novo or restenotic lesions up to 180 mm in length located in native superficial femoral and proximal popliteal arteries (SFA/PPA) with reference vessel diameters of 4 mm to 7 mm.

Use of the Ranger DCB catheter is contraindicated in:

• Patients with known hypersensitivity to paclitaxel (or structurally-related compounds).
• Patients who cannot receive recommended antiplatelet and/or anticoagulation therapy.
• Women who are breastfeeding, pregnant or men intending to father children.
• Patients judged to have a lesion that prevents complete inflation of an angioplasty balloon or proper placement of the delivery system.
• Coronary arteries, renal arteries, and supra-aortic/cerebrovascular arteries.

• Never use air or any gaseous medium to inflate the balloon (a 50:50 mixture of contrast medium and sterile saline is recommended).
• When the balloon catheter is exposed to the vascular system, it should be manipulated while under high-quality fluoroscopic observation.
• Do not advance or retract the catheter unless the balloon is fully deflated under vacuum.
• If unusual resistance is felt during manipulation, determine the cause of the resistance before proceeding. If the source of resistance cannot be determined, it is recommended to extract the entire system with the guiding sheath.
• If difficulty is experienced during balloon inflation, do not continue. Deflate the balloon and remove the catheter.
• To reduce the potential for vessel damage, the inflated diameter of the balloon should approximate the diameter of the vessel segment to be treated. The inflated length of the balloon (shoulder to shoulder) may exceed the length of the lesion/stenosis by approximately 10 mm on either side within the targeted artery.
• Do not exceed the balloon rated burst pressure. Use of an inflation device is recommended to prevent over-pressurization.
• The safety of using multiple Ranger DCBs with a total drug dosage exceeding 9266 μg of Paclitaxel in a patient has not been studied.
• Using a drug-eluting stent in conjunction with Ranger DCB catheter at the same treatment site has not been studied.

Contents supplied STERILE using an ethylene oxide (EO) process. Do not use if sterile barrier is damaged. If damage is found, call your Boston Scientific representative.
For single use only. Do not reuse, reprocess or resterilize. Reuse, reprocessing or resterilization 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. Reuse, reprocessing or resterilization 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. Contamination of the device may lead to injury, illness or death of the patient.
After use, dispose of product and packaging in accordance with hospital, administrative and/or local government policy. See section “Disposal” for additional details regarding disposal of this medical device.

• The balloon catheter should be used only by physicians experienced in the performance of percutaneous transluminal angioplasty.
• Use the balloon catheter prior to the “Use By” date specified on the package.
• The balloon catheter should be used with caution for procedures involving calcified lesions due to the abrasive nature of these lesions.
• The balloon catheter is not intended for injection of contrast medium.
• Full arterial wall apposition of the Ranger DCB catheter is necessary for proper drug transfer to the vessel.
• Carefully inspect the balloon catheter prior to use to verify that it has not been damaged during shipment and that its size, shape and condition are suitable for the procedure for which it is to be used.
• If unusual resistance is felt during positioning of the loading tool, do not use the balloon catheter. Replace with a new Ranger DCB catheter.
• If unusual resistance is felt during catheter advancement through the valve, do not use the balloon catheter. Replace with a new Ranger DCB catheter.
• Do not touch, wipe, bend, or squeeze the balloon. Do not allow it to contact any liquids including organic solvents such as alcohol or detergents prior to insertion. Damage to the balloon coating or premature release of the drug may occur.
• To minimize the possible introduction of air into the system, it is imperative that prior to proceeding, careful attention is paid to the maintenance of tight catheter connections and thorough aspiration and flushing of the system.
• If using a Tuohy-Borst type adapter, take care not to over-tighten the hemostasis valve around the catheter shaft as lumen constriction may occur, affecting inflation/deflation of the balloon or damaging the drug coating.
• Never advance the balloon catheter without the guidewire extending from the distal tip.
• When using a sheath, do not insert the loading tool more than 20 mm into the sheath valve.
• This product should not be used in patients with uncorrected bleeding disorders or patients who cannot receive anticoagulation or antiplatelet aggregation therapy.
• If loading tool tip will not enter the guide / introducer sheath valve, forcing the loading tool can cause catheter shaft kinking and damage to drug coating when advancing the catheter. Consider replacing guide / introducer sheath.
• If treating a long lesion (longer than the maximum balloon length available), each individual segment should be treated only once with a drug-coated balloon. Treat each segment with a new balloon and minimize overlapping of treated segments.
• Used devices may pose a biohazard risk and must be handled and disposed of properly.

Pregnancy / Lactation
This product has not been tested in pregnant or breastfeeding women or in men intending to father children; effects on the developing fetus have not been studied and the risks and reproductive effects remain unknown.
It is not recommended that the Ranger DCB catheter be used in women attempting to conceive, or who are pregnant. Prior to use, careful consideration should be given to the continuation of breastfeeding, taking into account the importance of the procedure to the mother. It is not known whether paclitaxel is distributed in human milk. In lactating rats, milk concentrations appeared to be higher than maternal plasma levels and declined in parallel with the maternal levels. Mothers should be advised of the potential for serious adverse reactions to paclitaxel in nursing infants.

Drug Information
The mechanism of action by which paclitaxel reduces or reverses neointima formation and proliferation, leading to restenosis, as demonstrated in clinical studies has not been established.
It is known that paclitaxel promotes the assembly of microtubules from tubulin dimers and stabilizes microtubules by preventing depolymerization. This stability results in the inhibition of the normal dynamic reorganization of the microtubule network that is essential for vital interphase and mitotic cellular functions.

Drug Interaction
Possible interactions of paclitaxel with concomitantly administered medications have not been formally investigated. Drug interactions of systemic chemotherapeutic levels of paclitaxel with possible concomitant medications are outlined in the labeling for finished pharmaceuticals containing paclitaxel, such as TAXOL.

Carcinogenicity, Genotoxicity, and Reproductive Toxicology
No long-term studies in animals have been published in peer reviewed literature to evaluate the carcinogenic potential of paclitaxel. Paclitaxel interacts with microtubules; this is the major mechanism by which it inhibits cell growth. One consequence is the loss of whole chromosomes via interactions with spindle microtubules during cell division. As such, paclitaxel is defined as an aneugen (agent causing an alteration in chromosome number). This indirect action is consistent with positive responses in in vitro and in vivo micronucleus genotoxicity assays, which detect DNA fragments. Positive results have also been reported for chromosomal aberrations in primary human lymphocytes. It is not known whether paclitaxel has a separate direct action on DNA in the generation of DNA strand breaks or fragments. It is negative in assays for gene mutation, including salmonella and CHO/HPRT. Paclitaxel administered via IV prior to and during mating produced impairment of fertility in male and female rats at doses > 1 mg/kg. Administration of paclitaxel during the period of organogenesis to rabbits at doses of 3 mg/kg/day caused embryo- and fetotoxicity. Maternal toxicity was also observed at this dose. No teratogenic effects were observed at 1 mg/kg/day; teratogenic potential could not be assessed at higher doses due to extensive fetal mortality. For comparison, the worst-case dose of paclitaxel delivered by the Ranger DCB catheter (assuming maximum size and number of balloons used in a lesion) is 9266 μg, which is approximately 6 and 19 times less than the dose that saw effects in rats and rabbits, respectively, when normalizing to body weight.

Pre and Post Procedure Antiplatelet Therapy
It is strongly advised that the treating physician follow the Inter-Society Consensus (TASC II) Guidelines recommendations (or other applicable country guidelines) for antiplatelet therapy pre- and post-procedure.

Potential adverse events include, but are not limited to, the following:

• Allergic reaction (device, contrast medium, medications)
• Death
• Embolism (air, plaque, thrombus, device, tissue, other)
• Hematoma
• Hemorrhage/Bleeding
• Hypotension/Hypertension
• Infection/Sepsis
• Restenosis of the treated vessel
• Thrombosis/Thrombus
• Vasospasm
• Vessel occlusion
• Vessel trauma (e.g. dissection, perforation, pseudoaneurysm, rupture, arteriovenous fistula)

Potential adverse events not captured above that may be unique to the paclitaxel drug coating:

• Allergic/immunologic reaction to drug (paclitaxel or structurally-related compounds) or coating or its individual components
• Alopecia
• Anemia
• Blood product transfusion
• Gastrointestinal symptoms
• Hematologic dyscrasia (including leukopenia, neutropenia, thrombocytopenia)
• Hepatic enzyme changes
• Histologic changes in vessel wall, including inflammation, cellular damage or necrosis
• Myalgia/Arthralgia
• Peripheral neuropathy

Apart from hypersensitivity reactions (allergic/immunologic reactions), the likelihood of paclitaxel related adverse events is low, due to the low exposure.
There may be other potential adverse events that are unforeseen at this time.