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Full Prescribing Information

This page contains Full Prescribing Information from the LIPOSORBER System Package Insert.

1. INTRODUCTION

This operator's manual is intended to be a reference for proper and safe operation of the MA-03. In no way is this manual intended to be a step-by-step guide in the actual decisions regarding the treatment of the patients.

For proper and safe operation, be sure to carefully read this operator's manual before use. Keep this manual by the machine for immediate reference.

1.1. DESCRIPTION

The LIPOSORBER® LA-15 System is an integrated, automated extracorporeal blood processing system that includes the following 3 disposables and a control/monitor machine:

LIPOSORBER® LA-15 LDL Adsorption Column set (disposable) consisting of two columns, each containing 150 ml of dextran sulfate cellulose adsorbent;

SULFLUX® KP-05 Plasma Separator (disposable) containing hollow fibers made of polyethylene coated by an ethylene-vinyl alcohol copolymer;

Tubing System for Plasmapheresis (NK-M3R(U)) (disposable); and

the Apheresis Machine KANEKA MA-03, which monitors and controls the LDL-apheresis procedure.

Caution: Federal law restricts this device to sale, distribution and use by or on the order of a licensed physician with appropriate training.

This system may be used only as prescribed by a licensed and appropriately trained physician. While connected to the extracorporeal system, the patient must be attended at all times by a physician or qualified health-care professional adequately trained in all aspects of the procedure. All physicians and medical personnel utilizing the LIPOSORBER® LA-15 System will be required to have completed an appropriate training program.

1.2. INDICATIONS FOR USE

The LIPOSORBER® LA-15 System is indicated for use in performing low density lipoprotein cholesterol (LDL-C) apheresis to acutely remove LDL-C from the plasma of the following high risk patient populations for whom diet has been ineffective and maximum drug therapy has either been ineffective or not tolerated:

Group A: Functional Hypercholesterolemic Homozygotes with LDL-C > 500 mg/dL;
Group B: Functional Hypercholesterolemic Heterozygotes with LDL-C ≥ 300 mg/dL; and
Group C: Functional Hypercholesterolemic Heterozygotes with LDL-C ≥ 160 mg/dL and either documented coronary heart disease or documented peripheral arterial disease.

The LDL-C levels for the indicated patient populations are baseline LDL-C levels obtained after the patient has had, at a minimum, a six-month trial of an American Heart Association (AHA) Step II diet (or equivalent) and maximum tolerated combination drug therapy designed to reduce LDL-C. Maximum tolerated combination drug therapy is an adequate trial of drugs from at least two separate classes of hypolipidemic agents such as, bile acid sequesterants, HMG-CoA reductase inhibitors, fibric acid derivatives, Niacin/Nicotinic Acid, etc. Documented coronary heart disease (CHD) includes documentation of coronary artery disease by coronary angiography or a history of myocardial infraction (MI), coronary artery bypass surgery (CABG), percutaneous transluminal coronary angioplasty (PTCA) or alternative revascularization procedure (e.g. atherectomy or stent), or progressive angina documented by exercise or non-exercise stress test. Documented peripheral arterial disease (PAD) includes documentation of peripheral arterial disease based on the symptom (e.g. Category 1 through 6 of the Rutherford classification) or a history of the treatment (e.g. peripheral angioplasty, bypass surgery, minor or major amputation). Baseline lipid levels are to be determined after stabilization on diet and drug therapy by making two measurements during a 2 to 4 week period. (Note: The two values should be within 10% of each other, indicating a stable condition.)

Although clinical benefit of LDL-C lowering has been documented in several diet, drug and/or surgical intervention trials, clinical studies using the LIPOSORBER® LA-15 System were not designed to address and did not establish the long-term benefit of acutely lowering LDL-C.

1.3.  CONTRAINDICATIONS

LDL apheresis with the LIPOSORBER® LA-15 System is contraindicated in patients:

(a) for whom the use of heparin would cause excessive or uncontrolled anticoagulation or for whom adequate anticoagulation cannot be safely achieved, such as patients with hemophilia or patients who have had recent surgery; or

(b) with known hypersensitivity to heparin or ethylene oxide.

1.4. WARNINGS
  1. The safety of LDL-apheresis treatment with the LIPOSORBER® LA-15 occurring more than once a week or for treated volumes larger than two plasma volumes has not been determined.

     

  2. Patients who have received an ACE (angiotensin converting enzyme) inhibitor within the last 24 hours should not be treated. Therefore, the physician must monitor the use of ACE inhibitor medication on an ongoing basis with each treatment. Patients receiving an ACE inhibitor may experience an anaphylactoid-like reaction, including hypotension associated with flushing, dyspnea, and bradycardia. Such reactions, if left untreated, may be life-threatening. The administration of ACE inhibitors also has been associated with the occurrence of tachycardia. Risk of an anaphylactoid-like reaction or tachycardia may be minimized by the temporary cessation of the administration of ACE inhibitors for 24 hours or longer before each LDL-apheresis procedure depending upon whether the ACE inhibitor is a short- or long-acting dosage form.

     

  3. LDL-apheresis treatment of patients who have taken any antihypertensive drugs within 24 hours of treatment may cause hypotension in such patients. When clinically feasible, patients should not receive antihypertensive drugs during the 24 hour period prior to undergoing the LDL-apheresis procedure. Before each treatment, physicians should determine when patients took their last dose of such medication.

     

  4. Before using the LIPOSORBER® LA-15 System, carefully review the Operator's Manual. Persons performing the procedures must be qualified and have completed the required training program. Users should follow all operating or maintenance procedures published by Kaneka Pharma America LLC and use only those disposable device components recommended by Kaneka Pharma America LLC. To do otherwise may result in injury or loss of life.

     

  5. Prior to initiating an LDL-apheresis procedure, carefully review the package inserts for all disposables and other materials to be used during the procedure. Failure to comply strictly with such package inserts, including the instructions for use, may result in serious injury to or possible death of patients.

     

  6. Use special caution in patients where the extracorporeal volume of approximately 400 ml potentially will exceed 10% of the patient's blood volume. Such patients are at higher risk of experiencing hypovolemia, which is sometimes followed by hypotension.

     

  7. Do not apply whole blood directly to the LIPOSORBER® LA-15 LDL Adsorption Column. This device is designed for perfusion of plasma only.

     

  8. Citrate preparatiCitrate preparation (ACD) should never be used as an anticoagulant in the system. The MA-03 is designed solely for treatment using heparin as an anticoagulant. Anticoagulation is required to prevent thrombus formation from occurring within the extracorporeal circuit. Anticoagulation with too much heparin is associated with an increased risk of bleeding for the patient, especially after the procedure. In order to reduce the risk of bleeding, the puncture sites should be sufficiently compressed so that bleeding is stopped. (See Section 1.6.1 (7) Notes for Potential Adverse Reactions.) In some patients the potential for development of a coagulopathy extending several days post-therapy may exist. In addition to adjusting heparin dosage based on clinical observation during and after the apheresis procedure, Activated Clotting Time and/or partial thromboplastin time (PTT) values may be used(See Section 1.8 Instructions for Use regarding "Determining Heparin Dosage.")

     

  9. Make sure that the plasma flows in the direction of the arrow on the label of the LIPOSORBER® LA-15 Adsorption Columns.

     

  10. Rinsing and subsequent priming of the fluid pathway of the disposables with appropriate solutions are necessary before commencing the procedure. Because air bubbles in the disposables may lead to complications such as coagulation of plasma and impairment of performance, give full attention to measures that will prevent air-bubble migration into the disposables during rinsing and priming.

     

  11. During an LDL-apheresis procedure, 0.9% Sodium Chloride Injection, USP, 5% Sodium Chloride Injection, USP, Lactated Ringer's Injection, USP, and Heparin Sodium Chloride Injection, USP, are used. Carefully identify each solution and ensure that it is properly connected to the LIPOSORBER® LA-15 System. Using the incorrect solution may result in serious injury or possible death.

     

  12. While operating, the differential pressure across the LIPOSORBER® LA-15 Adsorption Column must be under 100 mmHg, and the transmembrane pressure (TMP) of the SULFLUX® KP-05 Plasma Separator must be under 60 mmHg. If either an extreme pressure drop across the column or an extreme TMP occurs, the blood flow rate and/or plasma separation rate should be lowered appropriately or even stopped if necessary.

     

  13. To minimize the risk of air embolism, the return tubing line must be connected to the air bubble detector.

     

  14. In case of a power failure or system shutdown, terminate the procedure immediately according to the instructions provided in Chapter 7.6 Manual Blood Return of the the Operator's Manual for the LIPOSORBER® LA-15 System.

     

  15. No chemicals or solvents are to be used either inside or outside of the disposables.
1.5. PRECAUTIONS
  1. The long-term safety and efficacy of LDL-apheresis using the LIPOSORBER® LA-15 System have not been established. (See Section 1.7 Clinical Experience.)

     

  2. The safety and efficacy of LDL-apheresis using the LIPOSORBER® LA-15 System has not been established for pregnant women or for women during the lactation period, e.g. the effect of treatments on folic acid levels has not been determined.

     

  3. The safety and efficacy of LDL-apheresis using the LIPOSORBER® LA-15 System have not been established for: (1) patients less than 15 kg in body weight; (2) patients less than 5 years of age; (3) patients with certain cardiac impairments such as uncontrolled arrhyth­mia, unstable angina, decompensated congestive heart failure or valvular disease; and (4) patients with renal or thyroid disease or liver abnormalities.

     

  4. LDL-apheresis should be considered a lifetime therapy since, upon discontinuation of therapy, lipid levels will return to pre-treatment levels or higher. Diet and drug therapy must be main­tained during the treatment period as the rate of rebound will accelerate if lipid-lowering drug therapy is discontinued.

     

  5. The SULFLUX® KP-05 Plasma Separator, LIPOSORBER® LA-15 Adsorption Column, and the Tubing System forAphere­sis (NK-M3R(U)) are disposable and are intended for use in a single procedure only. Never reuse. Discard all used and unused disposables after each procedure.

     

  6. Physicians and operators should follow the OSHA and the CDC/ACIP Adult Immunization Guidelines for Hemodialysis Patients. It is recommended that patients be screened for Hepatitis B and other infectious diseases; however, due to possible exposure to hepatitis virus, human immunodeficiency virus, and other infectious agents when handling extracorporeal blood circuits, blood or blood products, universal precau­tions should be taken at all times to prevent the exposure to and transmis­sion of such agents.

     

  7. When disposing of the disposable device components and wastes, comply with all local requirements and the policy of the facility regarding precautions for and prevention of infection and environmental pollution.

     

  8. Medical personnel should monitor the patient for adverse symptoms at all times during treatment and should be trained as to the protocol for responding with appropriate inter­ventions. (See Section 1.6.1 Notes for Potential Adverse Reactions)

     

  9. Closely monitor patient clotting time periodically during the proce­dure to ensure that an adequate level of anticoagulation is maintained.

     

  10. Patient’s cholesterol levels (TC, LDL-C, HDL-C, etc.) should be monitored every 3 months during the course of long-term therapy. Samples for cholesterol levels should be taken immediately before and after a given LDL-apheresis procedure.

     

  11. High density lipoprotein cholesterol (HDL‑C) may be acutely reduced by up to 14% post-treatment. Epidemiologic studies have shown that both low HDL-C and high LDL-C are independent risk factors for coronary heart disease. The risk of acutely lowering HDL-C while lowering LDL-C with this device is unknown.

     

  12. Instructions for heparin administration should be followed as stated in the guidance pro­vided by the manufacturer in the Operator’s Manual for the LIPOSORBER® LA‑15 System. The amounts of heparin outlined in the Operator’s Manual are intended as general suggestions. The exact amount, frequency and method of administration of heparin are the sole responsibility of the prescribing/attending physician and should be selected based on the individual patient’s clinical condition.

     

  13. All connections of the extracorporeal circuit should be checked carefully prior to initiating and during the proce­dure. Avoid unnecessary kinking of the tubing lines and the patient’s vascular access devices at all times.

     

  14. The transducer protectors must be attached and locked to the machine and tubing lines. Strict aseptic technique should be used during this and all procedures. After the completion of the procedure, properly dispose of all used and unused transducer protectors. Do not reuse.

     

  15. Drip chambers in the infusion line in the extracorporeal circuit should be kept at least 2/3 to 3/4 full and monitored at all times in order to decrease the risk of air embolism.

     

  16. Each tubing line must be properly connected and cleared of air, prior to the start of Rinse. Do not allow air to be trapped in the set. Puncturing tubing lines may cause air embolism.

     

  17. The fluid circuit of this system is intended to be sterile and nonpyrogenic. Aseptic handling techniques are necessary to maintain these conditions. Check the packaging for the disposable device components to ensure that it is intact. Do not use a disposable product if the package, sterile bag, protective cap or the product itself is damaged. Do not open the sterile bags containing the disposables until use.

     

  18. The LIPOSORBER® LA‑15 System includes a blood warmer with a temperature setting range of 35-40° C. It is recommended that the blood warmer be set at a temperature between 36‑38° C in order to avoid significant decreases in blood temperature during extracorporeal circulation.

     

  19. In transporting and storing the device components, handle with care and store all disposables in a clean and secure area at room temperature (5‑30° C), avoiding exposure to direct sunlight, high humidity or excessive vibration. Handle the SULFLUX® KP-05 Plasma Separator and the LIPOSORBER® LA‑15 Adsorption Columns with care to avoid dropping or other sudden impacts and never allow them to freeze. Do not use components which may have been damaged or frozen.
1.6. ADVERSE EVENTS

During the course of the clinical study from December 1988 through June 1995, 74 patients1 had received 4,936 treatments using the LIPOSORBER® LA-15 System.Prior to enrollment in the clinical study, 76% of the patients had documented coronary heart disease, and 26% of all patients previously had a myocardial infarction. Upon enrollment in the clinical study, 74% of the patients had LDL-cholesterol levels exceeding 200 mg/dl after diet and maximum drug therapy. Patients who were receiving or had received LDL-apheresis therapy with the LIPOSORBER® LA-15 System experienced the following adverse events:

Patients in the clinical study experienced the following adverse events during LDL-apheresis procedures using the LIPOSORBER® LA-15 System:

 

Table 1.1. - Adverse Events Experienced During LDL-Apheresis Procedures

 

Adverse Events Episodes Patients
Hypotension 41 0.8% 25 33.8%
Nausea/Vomiting 27 0.5% 14 18.9%
Flushing/Blotching 20 0.4% 9 12.2%
Angina/Chest Pains 10 0.2% 8 10.8%
Fainting 9 0.2% 6 8.1%
Lightheadedness 7 0.1% 6 8.1%
Anemia 6 0.1% 6 8.1%
Abdominal Discomfort 5 0.1% 3 4.1%
Numbness/Tingling 4 0.1% 4 5.4%
Tachycardia 4 0.1% 3 4.1%
Headache 3 0.1% 3 4.1%
Shortness of Breath 3 0.1% 2 2.7%
Hemolysis 3 0.1% 2 2.7%
Bradycardia 3 0.1% 2 2.7%
Itching/Hives 2 0.04% 2 2.7%
Blurred Vision 2 0.04% 2 1.4%


Single incidents of the following adverse events also occurred: Arrhythmia; vasovagal reaction; bleeding (prolonged); chills; diaphoresis; and blood loss.

1 Included in this patient total are one emergency use patient treated for nephrotic syndrome (FGS) and one patient with coronary heart disease treated under a special IDE supplement for an elevated Lp(a) level.

Deaths

Six patients who had been enrolled in the clinical study between December 1988 through January 1996 died:

Forty-four year old male died on September 30, 1992 from congestive heart failure resulting from preexisting supravalvular aortic stenosis and coronary artery disease. Patient had ceased receiving LDL-apheresis treatment more than a year earlier.

Seventeen year old male, who had received 226 treatments, died on May 14, 1995 from blunt trauma to the head suffered as a result of an accidental fall from a window after consuming alcohol.

Seventy-two year old male, who had received 150 LDL-apheresis treatments, died on January 13, 1996, apparently from a heart attack resulting from severe, preexisting coronary heart disease, including two prior myocardial infarctions, a stroke, and two coronary artery bypasses.

Sixty-one year old male, who had received 14 LDL-apheresis treatments, died in the spring of 1990, from a malignant glioma of the brain.

Sixty-one year old male who had received 96 treatments and had multiple risk factors, including cerebrovascular disease with prior ischemic injury to brain, left ventricular mural thrombus, and hyper­tension, died on September 22, 1994 of cerebral hemorrhage.

Fifty year old male, who had smoked two packs of cigarettes per day for more than 30 years, died on April 22, 1990 of lung cancer with metastases to the liver.

None of these deaths occurred during an LDL-apheresis treatment, and the clinical investigators for the patients did not identify LDL-apheresis as a causal factor. However, it cannot be concluded with certainty, due to the small size of the patient groups and the lack of a control group, whether any of the deaths were treatment related.

Myocardial Infarctions

During the course of the clinical study, three MI occurred: Two occurred in patients who were no longer receiving treatment. No MI occurred during an actual LDL-apheresis pro­cedure, and the clinical investigators for the patients did not identify LDL-apheresis as a causal factor. The pos­sibility that there is an increased risk of angina or MI in patients receiving this therapy cannot be totally excluded.

Other Potential Adverse Events

Although patients participating in the clinical study did not experience the following adverse events during the reported 4,936 treatments, such events may occur in procedures involving extracorporeal circulation: uncontrolled bleeding; infectious disease transmission, including hepatitis; sepsis due to circuit contamination; air embolism, and hypersensitivity reactions.

Other complications may include: plasma loss from circuit leaks; coagulopathy potentially extending several days post treatment; and volume shifts. Equipment mal­function or user error may result in fluid volume abnormalities which may require acute medical intervention.

Patients on antihypertensive drugs, such as diuretics, calcium antagonists, beta blockers and ACE inhibitors, are at increased risk of hypotensive reactions occurring during therapy. ACE inhibitors have been associated with severe hypotension associated with flushing, dyspnea, and bradycardia. Therefore, ACE inhibitors should not be administered for 24 hours or longer preceding each apheresis procedure. (See Warnings.) In order to minimize the potential risks which also may be associated with other anti-hypertensive medications, it is recommended that patients refrain from taking anti-hypertensive drugs at least the day before the LDL-apheresis procedure, when clinically feasible. Before each treatment, patients should be requested to advise the attending physician when they last took a dose of such medication. One of the hypotensive events reported in Table 1.1 was attributed to the administration of ACE inhibitors. The administration of ACE inhibitors in conjunction with therapy with the device also has been associated with the occurrence of tachycardia, and three of the reported tachycardia events (two in an emergency use patient) were attributed to the administration of ACE inhibitors.

Reduction in Serum Components

LDL-apheresis is known to decrease the selected serum components listed below. The long-term effects of such reduction have not been established.

Table 1.2. - Reduction in Serum Components

Serum Component
Acute Percentage Reduction (%)
Hemoglobin
1.4
Vitamin E (a-tocopherol)*
63
Vitamin E (y-tocopherol)*
55
Albumin
14
Fibrinogen
29
Platelets
17


* Data for the acute reductions in these serum components also included limited data from follow-up treatments.

1.6.1. Notes for Potential Adverse Events

If a patient experiences an adverse reaction during a procedure, the physician should stop the procedure until the cause of the reaction has been determined and the patient's condition stabilized. The physician should determine all medical responses to adverse reactions based upon the individual patient's physical condition. However, certain reactions that may be anticipated are identified below with common medical treatment responses.

  1. Hypotension.
    The procedure should be stopped, and the patient should be placed in the Trendelenburg position and/or receive a fluid challenge. If the hypotension persists, the procedure should be terminated.
    Note:
    For an "anaphylactoid" like reaction, administration of epinephrine, sympathomimetic drugs, prednisolone, anti-histamines, and/or calcium have been reported by clinicians as effective interventions

     

  2. Nausea and Vomiting.
    The procedure should be stopped and the etiology of the nausea and vomiting investigated (e.g. hypotension).

     

  3. Flushing/Blotching.
    Check vital signs and reduce the blood flow rate. If symptoms are persistent or repetitive, consider the administration of Benadryl.

     

  4. Angina/Chest Pain. The procedure should be stopped and medical therapy instituted at the discretion of the physician. If the angina persists, the procedure should be terminated.

     

  5. Fainting/Lightheadedness See hypotension.

     

  6. Anemia.
    May be minimized by the appropriate use of iron supplements. Clinical symptoms may appear when hemoglobin is below 11 g/dl in men and 10 g/dl in women.

     

  7. Prolonged Bleeding (at cannulation site after removing venous cannulae).
    Direct manual pressure should be applied until the bleeding stops. If prolonged bleeding occurs (in excess of 20 minutes), adjustment of the heparin dosing may be necessary. It is recommended that, during the subsequent procedure, the heparin dose be reduced and monitored by Activated Clotting Time (ACT). Repetitive LDL apheresis treatment may affect the patient's clotting time. Therefore, a periodic check, e.g. every 3 months, of other relevant coagulation parameters is recommended, including the number of thrombocytes and the fibrinogen concentration, in order to ensure that these parameters are sufficient to maintain adequate coagulation.

     

  8. Hemolysis as Evidenced by Discoloration of Plasma or Hemolysis as Indicated by Activation of the Blood Leak Detector Alarm of the MA-03.
    If either indicator of hemolysis occurs, the procedure should be terminated and the patient's hematocrit, urine output and kidney function monitored.
1.7. CLINICAL EXPERIENCE

The clinical study of the LIPOSORBER® LA-15 System was conducted at 11 clinical sites in the United States with 72 patients (of whom 47 patients were within the indicated patient population identified in Section 1.2 and 35 were treated for a minimum of 11 months), and data were reported for 4,687 LDL-apheresis procedures performed from December 14, 1988 through June 30, 1995. The clinical patient population did not include pregnant women; patients less than 15 kg in body weight; patients less than 5 years of age; and patients with end stage renal disease, thyroid disease or liver abnor­malities. Under the clinical protocol, a 6‑week period of base­line stabilization was followed by a 22‑week study period consisting of 18 weeks of treatments, which were divided into 3 courses of 6 weeks each, and a 4‑week rebound study during which the change in lipid levels on diet and drug therapy were observed. During the study period, patients were maintained on diet and maximum tolerated lipid-lowering drug therapy and treated with the LIPOSORBER® LA-15 System, typically once every week for Group A and Group B patients and once every 2 weeks for Group C patients. There­after, patients were offered the oppor­tunity to continue to receive LDL-apheresis therapy.

Detailed effectiveness data were reported and statistically analyzed from 2,229 LDL-apheresis procedures performed from December 14, 1988 through September 30, 1991 in 64 patients (of whom 39 patients were within the indicated patient population identified in Section 1.2 and 29 were treated for a minimum of 11 months). The clinical study of these patients demon­strated that treatment with the LIPOSORBER® LA-15 System resulted in an acute lowering of LDL‑C of approximately 75% to 80%. How­ever, the LDL‑C levels rebounded at a nonlinear rate (more rapidly immediately post-treatment) as shown. (Table 1.4)

Adverse events data were reported for 74 patients1 and 4,936 treatments performed from December 14, 1988 through June 30, 1995. The adverse events experienced by these 74 patients during LDL-apheresis procedures with the LIPOSORBER® LA‑15 System are summarized in Table 1.1 above. All deaths and myocardial infarctions experienced by patients who were treated with the LIPOSORBER® LA-15 System during that time period also are reported in Section 1.6 Adverse Events.

1Included in this patient total are one emergency use patient treated for nephrotic syndrome (FGS) and one patient with coronary heart disease treated under a special IDE supplement for an elevated Lp(a) level.

1.8. INSTRUCTIONS FOR USE

The LIPOSORBER® LA-15 System is indicated for use in performing low density lipoprotein cholesterol (LDL-C) apheresis to acutely remove LDL-C from the plasma of the following high risk patient populations for whom diet has been ineffective and maximum drug therapy has either been ineffective or not tolerated:

Group A: Functional Hypercholesterolemic Homozygotes with LDL-C > 500 mg/dL;
Group B: Functional Hypercholesterolemic Heterozygotes with LDL-C ≥ 300 mg/dL; and
Group C: Functional Hypercholesterolemic Heterozygotes with LDL-C ≥ 160 mg/dL and either documented coronary heart disease or documented peripheral arterial disease.

The LDL-C levels for the indicated patient populations are baseline LDL-C levels obtained after the patient has had, at a minimum, a six-month trial of an American Heart Association (AHA) Step II diet (or equivalent) and maximum tolerated combination drug therapy designed to reduce LDL-C. Maximum tolerated combination drug therapy is an adequate trial of drugs from at least two separate classes of hypolipidemic agents such as, bile acid sequesterants, HMG-CoA reductase inhibitors, fibric acid derivatives, Niacin/Nicotinic Acid, etc. Documented coronary heart disease (CHD) includes documentation of coronary artery disease by coronary angiography or a history of myocardial infraction (MI), coronary artery bypass surgery (CABG), percutaneous transluminal coronary angioplasty (PTCA) or alternative revascularization procedure (e.g. atherectomy or stent), or progressive angina documented by exercise or non-exercise stress test. Documented peripheral arterial disease (PAD) includes documentation of peripheral arterial disease based on the symptom (e.g. Category 1 through 6 of the Rutherford classification) or a history of the treatment (e.g. peripheral angioplasty, bypass surgery, minor or major amputation). Baseline lipid levels are to be determined after stabilization on diet and drug therapy by making two measurements during a 2 to 4 week period. (Note: The two values should be within 10% of each other, indicating a stable condition.)

Effectiveness of the therapy will be influenced by the treatment frequency and the amount of plasma treated.

Determining Treatment Frequency:

Prior to initiation of therapy, baseline lipid levels should be determined after stabilization on maximum diet and drug therapy by taking two measurements during a two to four week period. (Note: The two values should be within 10% of each other to be acceptable.)

Treatment with LDL-apheresis provides an immediate acute reduction in a patient's lipid levels compared to pre-treatment lipid levels. The acute effects of an LDL-apheresis treatment on serum lipids and lipoproteins may be summarized as follows:

Table 1.3. - Acute Percentage Reductions In Lipids And Lipoproteins
Achieved During The Study Period Of The Clinical Trial Of The LIPOSORBER® LA-15 System.

Lipid/Lipoprotein Acute Percentage Reduction (%)
Total Cholesterol 61-71
LDL-C 73-83
HDL-C 3-14
Lp(a) 53-76
Triglycerides 47-68


Therapy with the LIPOSORBER® LA-15 System does not produce a sustained lowering of lipid levels. A patient's LDL-C level will increase (or rebound) immediately after treatment at a nonlinear rate (more rapidly immediately post-treatment) as shown in the following table:


Table 1.4. - Rebound Of LDL-C After Treatment During Study Period.

No. of Days after Treatment 

Cumulative Mean Percentage
Rebound to Baseline (%)

Group A
(N* =5)
Group B
(N =10)
Group C
(N =22)** 
1 9 - 19 8 - 18 6 - 16
2 14 - 26 15 - 25 20 - 32
3 23 - 39 25 - 35 24 - 56
5 31 - 51 38 - 52 42 - 58
7 39 - 57 43 - 73 47 - 73
14 49 - 91 69 - 99 65 - 103


* N = number of patients
** Group C also included two control patients who were not included in this analysis of study patients.

With regular apheresis treatments, a patient's LDL-C level can be maintained below the baseline level. Without regular treatment, a patient's LDL-C level will rebound to the baseline level or higher. In addition, the rate of rebound shown above will accelerate if diet and lipid-lowering drug therapy is discontinued; therefore, a patient's diet and drug therapy must be maintained. Because of the heterogenous nature of Hypercholesterolemia, dosing and response to therapy vary among patients, resulting in the need for individualized treatment prescriptions. It is recommended that, shortly after the initiation of therapy, the physician measure a rebound curve for each patient to aid in determining the appropriate treatment interval. Rebound curves are determined by measuring the patient's lipid level immediately following treatment and at several intermediate points before the next treatment. If the patient changes or discontinues lipid-lowering medication while undergoing LDL-apheresis, the rebound curve should be reestablished.

The original clinical trial of 64 patients (29 indicated patients with greater than 11 months of therapy) using the LIPOSORBER® LA-15 System has suggested that patients in Groups A and B of the indicated population should be treated at a frequency of once every week, while patients in Group C should be treated once every two weeks as part of a life-long maintenance therapy.

Determining Plasma Volume to be Treated:

The clinical study has established that treating 1.5 patient plasma volumes during a single procedure will yield a 75% to 80% acute reduction in LDL-C. The plasma volume to be treated can be calculated as follows:

  1. Obtain the following patient information:
    Sex  (male or female)
    Height  (centimeters)
    Weight  (kilograms)
    Hematocrit  (%)
  2. Refer to the appropriate table below (male or female) and, using the patient's height and weight, locate the factor (number) at their intersection

     

  3. Multiply the factor determined in Step 2 by (100 - hematocrit).

     

  4. Round up the value from Step 3 to the nearest hundredth.This is the plasma volume to be treated.


    MALE

    Table 1.5. - Factor To Calculate Plasma Volume To Be Treated.

    140 82 84 86 89 92 95 99 104 109 114 121 128
    135 80 82 84 86 89 93 97 101 106 112 118 125
    130 77 79 81 84 87 90 94 99 104 110 116 123
    125 75 77 79 82 85 88 92 96 102 107 113 120
    120 73 74 77 79 82 86 90 94 99 105 111 118
    115 70 72 74 77 80 83 87 92 97 102 109 116
    110 68 70 72 74 77 81 85 89 94 100 106 113
    105 65 67 69 72 75 78 82 87 92 98 104 111
    100 63 65 67 69 72 76 80 84 89 95 101 108
    W 95 60 62 64 67 70 74 77 82 87 93 99 106
    E 90 58 60 62 65 68 71 75 80 85 90 97 103
    I 85 56 57 60 62 65 69 73 77 82 88 94 101
    G 80 53 55 57 60 63 66 70 75 80 85 92 99
    H 75 51 53 55 57 60 64 68 72 77 83 89 96
    T 70 48 50 52 55 58 61 65 70 75 81 87 94
    (kg) 65 46 48 50 53 56 59 63 67 73 78 84 91
    60 44 45 48 50 53 57 61 65 70 76 82 89
    55 41 43 45 48 51 54 58 63 68 73 80 87
    50 39 41 43 45 48 52 56 60 65 71 77 84
    45 36 38 40 43 46 49 53 58 63 69 75 82
    40 34 36 38 40 43 47 51 55 60 66 72 79
    35 31 33 35 38 41 45 49 53 58 64 70 77
    30 29 31 33 36 39 42 46 51 56 61 68 75
    25 27 28 31 33 36 40 44 48 53 59 65 72
    20 24 26 28 31 34 37 41 46 51 56 63 70
    15 22 24 26 28 31 35 39 43 48 54 60 67
    100 110 120 130 140 150 160 170 180 190 200 210

    Height (cm)


    FEMALE

    Table 1.6 - Factor To Calculate Plasma Volume To Be Treated
    140 78 79 81 84 87 90 94 98 103 109 115 122
    135 75 77 79 81 84 88 92 96 101 106 112 119
    130 73 74 76 79 82 85 89 93 98 104 110 117
    125 70 72 74 77 79 83 87 91 96 101 108 114
    120 68 69 72 74 77 80 84 89 93 99 105 112
    115 65 67 69 72 74 78 82 86 91 96 103 109
    110 63 64 67 69 72 75 79 84 88 94 100 107
    105 60 62 64 67 70 73 77 81 86 91 98 104
    100 58 59 62 64 67 70 74 79 84 89 95 102
    W 95 55 57 59 62 65 68 72 76 81 87 93 99
    E 90 53 55 57 59 62 65 69 74 79 84 90 97
    I 85 50 52 54 57 60 63 67 71 76 82 88 94
    G 80 48 50 52 54 57 60 64 69 74 79 85 92
    H 75 45 47 49 52 55 58 62 66 71 77 83 89
    T 70 43 45 47 49 52 56 59 64 69 74 80 87
    (kg) 65 40 42 44 47 50 53 57 61 66 72 78 84
    60 38 40 42 44 47 51 54 59 64 69 75 82
    55 35 37 39 42 45 48 52 56 61 67 73 80
    50 33 35 37 39 42 46 49 54 59 64 70 77
    45 30 32 34 37 40 43 47 51 56 62 68 75
    40 28 30 32 34 37 41 44 49 54 59 65 72
    35 25 27 29 32 35 38 42 46 51 57 63 70
    30 23 25 27 29 32 36 40 44 49 54 60 67
    25 20 22 24 27 30 33 37 41 46 52 58 65
    20 18 20 22 24 27 31 35 39 44 49 55 62
    15 16 17 19 22 25 28 32 36 41 47 53 60
    100 110 120 130 140 150 160 170 180 190 200 210

    Height (cm)

Example:

STEP 1: Obtain patient information.
Sex: Male
Height: 177 cm
Weight:  73 kg
Hematocrit: 38%
STEP 2: Use Table 1.5 (Male). Using the patient's height and weight, locate the factor at their intersection. Use next highest height (180 cm) and weight (75 kg). Factor 77
STEP 3: Multiply value from STEP 2 by (100 - hematocrit) 77 x (100 - 38) = 4,774
STEP 4: Round up value from STEP 3 to the nearest hundredth 4,800 ml
This is the plasma volume to be treated.


The amount of plasma treated and the frequency of treatment will require adjustment as clinically indicated by the physician in order to achieve and optimize individualized patient treatment goals. The patient should be maintained on diet and maximum tolerated lipid-lowering drug therapy. The patient should be clearly informed that if this therapy is to achieve continued acute lowering of LDL-C levels, it must be performed as part of a life-long treatment.

The safety of LDL-apheresis treatments performed more often than once a week or on volumes larger than two plasma volumes has not been determined.

Determining Heparin Dosage:

Although heparin administration procedures vary and are adjusted to the requirements of the individual patient by a supervising physician, a proper heparinization schedule must be initiated before and maintained throughout LDL-apheresis to prevent clotting and subsequent blood path obstruction. The following are examples of heparinization schedules.

  1. Priming Solution.
    Lactated Ringer's Injection, USP (1,000 ml) should contain 2,000-3,000 USP units of heparin.
  2. Loading Dose (Manual Infusion).
    Obtain PTT and PT pretreatment levels prior to initiation of LDL-apheresis therapy. If values are in the normal range, the recommended loading dose is approximately 25 USP units of heparin per kilogram of body weight. If a patient's PTT or PT is abnormally high, the physician should consider a lower loading dose of heparin.
  3. Continuous Heparinization.
    Continuous heparinization is required during the LDL-apheresis procedure. Based upon a normal PTT and PT, approximately 25 USP units of heparin per kilogram of body weight per hour is recommended. During the first few apheresis treatments, coagulation test results should be monitored frequently to establish a coagulation profile for the individual patient. A monitoring schedule for these initial treatments should consist of a pre-heparinization PTT, PT, and activated clotting time (ACT) measurement. The ACT measurements should be performed at 30-minute intervals during the treatment. ACT levels should be maintained within a range of 150 - 300 seconds or 1.5 to 3 times the normal range. Once a patient's heparin regimen has been established, a patient's ACT may be followed less frequently during subsequent treatments.

A heparin pump is used to deliver heparin into the blood withdrawal line at a rate necessary to maintain a desired clotting time. A heparin pump infusion rate between 1,000 - 3,000 USP units of heparin per hour usually is sufficient.

For an adult weighing 60 to 80 kg, a typical loading dose would be 1,500 to 2,000 USP units followed by a recommended continuous heparin rate of 1,500 to 2,000 USP units per hour.

Detailed Instructions for Use are set forth in the accompanying Operator's Manual for the LIPOSORBER® LA-15 System and in the package inserts for the LIPOSORBER® LA-15 Adsorption Column, SULFLUX® KP-05 Plasma Separator, and Tubing System for Plasmapheresis (NK-M3R(U)). The procedures outlined in the Operator's Manual must be followed exactly as specified. No adjustments or modifications of such procedures not specifically stated in the Operator's Manual may be made. In the event of equipment or device failure or malfunction, discontinue the procedure and follow the instructions in the Operator's Manual..

1.9. MOVING AND TRANSPORTATION OF THE MA-03

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1.9.1 Moving of the MA-03 Indoors

Normal Moving:

  1. Release the lock of casters.
  2. After that, the MA-03 can be moved or turned freely.

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Moving Over Different Floor Levels(i.e. Entrance of an elevator):

  1. To prevent damage or falling of the machine, always move the machine slowly while rolling over different floor levels or small bumps.

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1.9.2 Transportation of the MA-03 Outdoors

  1. The machine must not be moved across uneven surfaces (i.e., stone paved roads and the like).

     

  2. If the machine needs to be moved across an uneven surface, protect it from vibration by placing the machine on a sturdy handcart with proper padding.

     

  3. Before transporting the machine, remove all equipments and disposables such as solution bags, the external lamp and bag hangers.

     

  4. "Power Failure" buzzer sounds if POWER ON Button was accidentally pressed while transporting the machine.

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1.10. EMC INFORMATION

The MA-03 conforms to the EMC standard of IEC60601-1-2:2001

1.10.1 Electromagnetic Emission and Electromagnetic Immunity

The MA-03 is intended for use in the electromagnetic environment specified below. The customer or the user of the MA-03 should assure that it is used in such an environment.

Emissions test
Compliance
Electromagnetic environment - guidance
RF emissions CISPR 11 Group 1 The MA-03 uses RF energy only for its internal function. Therefore, its RF emissions are very low and are not likely to cause any interference in nearby electronic equipment.
RF emissions CISPR 11 Class A The MA-03 is suitable for use in all establishments other than domestic and those directly connected to the public low-voltage power supply network that supplies buildings used for domestic purposes.
Harmonic emissions
IEC 61000-3-2
Class A
Voltage fluctuations/ flicker emissions
IEC 61000-3-3
Complies

 

Guidance – electromagnetic immunity
Immunity test
IEC60601 test level
Compliance level
Electromagnetic environment - guidance
Electrostatic discharge(ESD)IEC 61000-4-2

±6kV contact

±8kV Air

±6kV contact

±8kV Air
Floors should be wood, concrete or ceramic tile. If floors are covered with aynthetic material, the relative humidity should be at least 30 %.

Electrical fast transient / burst

IEC 61000-4-4

±2kV for Power supply line

±1kV for input / output line

±2kV for Power supply line

±1kV for input / output line
Mains power quality should be that of a typical commercial or hospital environment.

Surge

IEC 61000-4-5

±1kV differential mode

±2kV common mode

±1kV differential mode

±2kV common mode
Mains power quality should be that of a typical commercial or hospital environment.

Voltage dips, short interruptions and voltage variations on power supply input lines

IEC 61000-4-11

<5% Ut
(>95% dip in Ut)
for 0.5 cycle

40% Ut
(60% dip in Ut)
for 5 cycle

70% Ut
(30% dip in Ut)
for 25 cycle

<5% Ut
(>95% dip in Ut)

for 5 s

5% Ut
(>95% dip in Ut)
for 0.5 cycle

40% Ut
(60% dip in Ut)
for 5 cycle

Mains power quality should be that of a typical commercial or hospital environment. If the user of the MA-03 requires continued operation during power mains interruptions, it is recommended that the MA-03 be powered from an uninterruptible power supply or a battery.

Power frequency
(50/60Hz) magnetic field

IEC61000-4-8
3A/m 3A/m Power frequency magnetic field should be measured in the intended installation location to assure that it is sufficiently low.
NOTE      Ut is the a.c. mains voltage prior to application of the test level.

 

Guidance – electromagnetic immunity
Immunity test
IEC60601 test level
Compliance level
Electromagnetic environment - guidance
Potable and mobile RF communications equipment should be used no closer to any part of the MA-03 including cables, than the recommended separation to the frequency of the transmitter.

Conducted RF IEC61000-4-6

3Vrms
(150kHz
to 80MHz)

3Vrms

Recommended separation distance
d=1.2√P

Radiated RF IEC61000-4-3

3V/m
80MHz
to 2.5GHz)

3V/m

d=1.2√P (80MHz to 800MHz)
d=2.3√P (800MHz to 2.5GHz)

where P is the maximum output power rating of the transmitter in watts (W) according to the transmitter manufacture and d is the recommended separation distance in meters (m)(√P is a square root of P.)
Field strengths from fixed RF transmitters, as determined by an electromagnetic site survey,”a” should be less than the compliance level in each frequency range.”b”

Interference may occur in the vicinity equipment maked with the following symbol:

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NOTE 1    At 80MHz and 800MHz, the higher frequency range applies.
NOTE 2    These guidelines may not apply in all situations. Electromagnetic propagation is affected by absorption and reflection from structures, objects and people.

"a" Field strengths from fixed transmitters, such as base stations for radio (cellular / cordless) telephones and land mobile ratios, amateur radio, AM and FM radio broadcast and TV broadcast cannot be predicted theoretically with accuracy. To assess the electromagnetic environment due to fixed RF transmitters, an electromagnetic site survey should be considered If the measured filed strength in the location in which the MA-03 is used exceeds the applicable RF compliance level above, the MA-03 should be observed to verify normal operation. If abnormal performance is observed, additional measures may be necessary, such as re-orienting or relocating the MA-03.

"b" Over the frequency range 150kHz to 80MHz, it is preferable that the field strengths should be less than 3 V/m.

 

1.10.2 Recommended separation distances between portable and mobile RF communications equipment and the MA-03

The MA-03 is intended for use in an electromagnetic environment in which radiated RF disturbances are controlled. The customer or the user of the MA-03 can help prevent electromagnetic interference by maintaining a minimum distance between portable and mobile RF communications equipment (transmitters) and the MA-03 as recommended below, according to the maximum output power of the communications equipment.

Rated maximum output power of transmitter
W

Separation distance according to frequency of transmitter
m

150kHz to 80MHz
d=1.2√P

80MHz to 800MHz
d=1.2√P

800MHz to 2.5GHz
d=2.3√P

0.01
0.12
0.12
0.23
0.1
0.38
0.38
0.73
1
1.2
1.2
2.3
10
3.8
3.8
7.3
100
12
12
23

For transmitters rated at a maximum output power listed above, the recommended separation distance d in meters (m) can be estimated using the equation applicable to the frequency of the transmitter, where P is the maximum output power rating of the transmitter in watts (W) according to the transmitter manufacturer.

NOTE 1
At 80MHz and 800MHz, the separation distance for higher frequency range applies.

NOTE 2
These guidelines may no apply in all situations. Electromagnetic propagation is affected by absorption and reflection from structures, objects and people.

1.11. THE MA-03 DANGER, WARNING AND CAUTION

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1.12. LIMITS TO THE MANUFACTURER'S RESPONSIBILITY
  • The LIPOSORBER® LA 15 System must be used in accordance with this Operator’s Manual. The use of operating or maintenance procedures other than those published by Kaneka Pharma America LLC or the use of disposable device components not recommended by Kaneka Pharma America LLC may result in injury or loss of life. Kaneka Pharma America LLC, the manufacturers of the MA-03 or the disposable device components, or any distributor of the LIPOSORBER® LA 15 System will not be responsible for resulting injury or damage if the procedures to operate and maintain the LIPOSORBER® LA 15 System are other than those specified by Kaneka Pharma America LLC in the Operator’s Manual. Persons performing the procedures must be appropriately trained and qualified.

  • In no event shall Kaneka Pharma America LLC or the manufacturers of the MA-03 or of the disposable device components or any distributor of the LIPOSORBER® LA 15 System be liable for any losses or damages caused or resulting from any negligence in the selection of patients outside the indicated population, operation of the LIPOSORBER® LA 15 System, or treatment of patients with the LIPOSORBER® LA 15 System by any third party.

  • Except as expressly set forth herein, Kaneka Pharma America LLC makes no warranty whatsoever, express or implied, and specifically disclaims any warranty of merchantability or fitness for a particular purpose as to the LIPOSORBER® LA 15 System.

  • In no event shall Kaneka Pharma America LLC, the manufacturers of the MA-03 or of the disposable device components or any distributor of the LIPOSORBER® LA 15 System be liable for any special, consequential or incidental losses or damages for any reason.

  • Certain solutions and disposable products available from other manufacturers are used with the LIPOSORBER® LA 15 System. Kaneka Pharma America LLC has no control over variability, tolerances, mechanical strength or changes in these products which may exist from time to time. Therefore, Kaneka Pharma America LLC cannot ensure that the disposable products of other manufacturers will function in a satisfactory manner and expressly disclaims any responsibility or liability for any injury, harm, damages or loss resulting from the use or malfunction of such products.
The information on this site is intended for U.S. residents only.
The information on this site does not replace your doctor's advice; only your doctor can assess the benefits and risks of therapy to determine whether LIPOSORBER® is right for you. Your doctor also can provide a complete description of reported side effects associated with this treatment.

 

© Copyright Kaneka Pharma America, LLC . All rights reserved.

The information on this site is intended for U.S. residents only.