Instructions for Use, Package Insert

Transcription

1 Disposable Probe for use with Her Option Cryoablation Therapy System Caution: U.S. Federal law restricts this device to sale by or on the order of a physician. Instructions for Use, Package Insert Package insert for USA use only. Device Description and Principle of Operation: Her Option is an office-based cryoablative treatment which uses a gas-cooled Cryoprobe to ablate the endometrial lining of the uterus. Its operation is based on the Joule-Thomson principle in which pressurized gas is expanded through a small orifice to produce cooling. The coolant or gas used in the system is a proprietary blend of commonly used coolants, which are non-toxic, non-corrosive, non-flammable and non-cfc. The system is intended to destroy tissue during ablation procedures by the application of extreme cold at the distal tip of the Cryoprobe. A -20 C temperature is lethal to tissue. The ice front advances through the uterine tissue, creating a CryoZone, rather than expanding within the endometrial cavity. Her Option includes a Console, a Cryoprobe and a Disposable Probe. The Cryoprobe with Disposable Probe attached is referred to as the Probe. A compressor housed in the Console is fully charged with coolant and is semi-hermetically sealed prior to shipping to ensure zero leakage. Activation of the System freeze cycle causes gas to exit the compressor and flow to the Probe where it expands to a low pressure across a small diameter orifice at the tip of the Probe. As a result, a rapid temperature drop occurs. This temperature drop is transferred to the tissue-contacting tip of the Disposable Probe, causing freezing. Gas then returns to the compressor and is recirculated. Deactivation of the freeze cycle stops gas flow to the Probe, ending cooling. The sterile Her Option Disposable Probe is sold separately. Her Option is supported for use in an office-based setting or the operating room. Indications: Her Option is a closed-cycle cryoablative device intended to ablate the endometrial lining of the uterus in premenopausal women with menorrhagia or excessive bleeding due to benign causes for whom childbearing is complete. Contraindications: The device is contraindicated for use in: A patient who is pregnant or who desires to become pregnant in the future. (Pregnancies following ablation can be dangerous for both mother and fetus). A patient with a known or suspected endometrial carcinoma (uterine cancer) or premalignant change of the endometrium such as unresolved adenomatous hyperplasia. A patient with an active genital or urinary tract infection at the time of the procedure (e.g., cervicitis, vaginitis, endometritis, salpingitis or cystitis). A patient with active pelvic inflammatory disease (PID). A patient with an intrauterine device (IUD) currently in place. A patient with any anatomic or pathologic condition e.g. chronic immunosuppressive therapy, in which weakness of the myometrium could exist, such as history of previous classical cesarean sections or transmural myomectomy Rev. N 2/15 1

2 Warnings: Failure to follow any instructions or to heed any warnings or precautions could result in serious patient injury. General Although endometrial ablation with Her Option significantly decreases the likelihood of pregnancy, it is not a sterilization procedure. The patient should be advised of appropriate birth control methods. Endometrial ablation does not eliminate the potential for endometrial hyperplasia, or adenocarcinoma of the endometrium and may mask the physician s ability to detect or make a diagnosis of such pathology. Patients who undergo endometrial ablation procedures who have previously undergone tubal ligation are at increased risk of developing post ablation tubal sterilization syndrome which can require hysterectomy. This can occur as late as 10 years post procedure. Technical Endometrial ablation procedures using Her Option should be performed only by medical professionals who have experience in performing procedures within the uterine cavity, such as IUD insertion or dilation and curettage (D&C) and who have adequate training and familiarity with use of Her Option. The sterile Her Option Disposable Probe is for single use only. Do not attempt to re-sterilize or reuse. Use caution not to perforate the uterine wall when sounding the uterus or inserting the Probe. If a perforation is present, the procedure should be terminated immediately. There is the potential for thermal injury to adjacent organs if the CryoZone extends beyond the serosal surface of the uterus; therefore, it is necessary to visualize and monitor the growth of the CryoZone with ultrasound. The freeze cycle should be stopped if the leading edge of the CryoZone approaches within 2mm the serosal surface. The risk of hematometra may be increased in cases where a "pull back" freeze is performed in the presence of incompletely ablated endometrium in the upper portions of the endometrial cavity. The duration of the pull back freeze should not exceed 4 minutes. To minimize the risk of cervical stenosis and hematometra, it is important that any 'pull back' freeze not ablate the internal os and/or endocervical canal. Because the freezing occurs along the distal 3-4 cm of the Cryoprobe, the minimum uterine sound length (including the cervical canal) required to perform a pull back is 8-9cm. Precautions: Endometrial ablation procedures using Her Option should be performed only by physicians trained in gynecologic ultrasound. It has been reported in the literature that patients with a severely anteverted, retroflexed or laterally displaced uterus are at greater risk of uterine wall perforation during any intrauterine manipulation. A false passage can occur during any procedure in which the uterus is instrumented, especially in cases of severely anteverted, retroflexed or laterally displaced uterus. Use caution to ensure that the device is properly positioned in the uterine cavity. Procedures breaching the endocervix, such as endometrial ablation, may seed the endometrium and the fallopian tubes with microorganisms found in the upper vagina and endocervix. Choosing prevention and treatment of these post procedural infections, either endometritis or pelvic inflammatory disease (PID), should take into consideration the polymicrobial nature of these infections (ref. ACOG Practice Bulletin No. 74, July 2006). Her Option is a sealed system. Tampering with the Console or Cryoprobe may result in loss of gas and loss of effectiveness. Clean and disinfect the stainless steel Cryoprobe according to instructions under Sterilization and Cleaning in the User s Manual. Do not autoclave. Do not immerse Cryoprobe in liquids. Do not use the Disposable Probe if there is any evidence of tampering or damage to the sterile package. It is very important that the PreCool cycle be conducted using the Disposable Probe that will be used for the treatment. Test Probes should NOT be used for PreCool cycle. To ensure that the system is operating properly, a PreCool cycle or a test freeze cycle should be conducted in air with every new Disposable Probe prior to placing the Probe in patient. If the Disposable Probe is switched during a procedure for any reason, a test freeze cycle in air should be initiated by pressing the minus (-) button immediately. Verify that the temperature reading on the console reaches - 50º C. Always monitor the temperature on the console display and verify that it is reading the temperature as expected (i.e., temperature is decreasing during cooling cycles and increasing during heating cycles). 2

3 Spark generation is possible: DO NOT use the system in an oxygen rich environment. Do not bend the Cryoprobe or the Disposable Probe. The Flexline is delicate and consists of four separate tubes each carrying fluids. Avoid sharp bending of the Flexline or pulling on the Flexline as a means of moving Her Option Console. If the power is interrupted during one of the freeze cycles or the display temperature fails to achieve 20 C use room temperature normal saline to accelerate the heating process and allow removal of the Probe. Do not attempt to disassemble Her Option Console, Cryoprobe or sterile Disposable Probe. DO NOT allow the ventilation holes on the Console to become obstructed, damage may occur. The Probe tip may become adherent to the tissue during freezing. Allow adequate time during the heat cycle for tissue to warm before attempting to remove the Probe (approximately 2 minutes, or when the temperature achieves 20 C). Do not attempt to remove Probe from tissue if there is significant resistance. If an error condition exists, use room temperature saline, rather than the heat cycle to loosen the Probe from the tissue. Patients who have undergone endometrial ablation and are later placed on hormone replacement therapy should have progestin included in their medication regimen in order to avoid the increased risk of endometrial adenocarcinoma associated with unopposed estrogen replacement therapy. The safety and effectiveness of Her Option for ablation of the endometrial lining of the uterus has not been fully evaluated in patients: with a uterus greater than 300cc in volume or a uterine sound greater than 10 cm, with a uterine sound less than 4 cm who have undergone a previous endometrial ablation procedure, who are planning to undergo or who have undergone transcervical sterilization (permanent birth control) procedures, with intramural myomas >3 cm in diameter, intrauterine polyps, or pedunculated fibroids, with a septate uterus, or, who are post-menopausal. Adverse Events: Her Option was evaluated in a randomized, prospective, multi-center clinical study, comparing Her Option Cryoablation Therapy to a control arm of rollerball endometrial ablation (REA). There were no reported incidents of serious device-related adverse events in the Cryoablation group. Tables 1a - 1c summarize the adverse events for the 272 patients treated in this study: Table 1a - Adverse Events During Procedure and within 24 hours Post-Procedure Adverse Event Cryoablation n=186 REA n=86 Uterine cramping 15 (8%) 4 (5%) Other abdominal or pelvic pain/cramping 27 (15%) 10 (12%) Nausea and vomiting 4 (2%) 4 (5%) Hot flashes 2 (1%) 0 (0%) Hyponatremia/Fluid Overload 0 (0%) 3 (3%) Perforation* 1 (0.5%) 1 (1%) Cervical/vaginal laceration 0 (0%) 1 (1%) *Cryo perforation occurred during sounding prior to treatment. REA perforation occurred during treatment. Table 1b - Adverse Events at 2 week Post-Procedure Adverse Event Cryoablation n=186 REA n=86 Uterine cramping 5 (3%) 0 (0%) Other abdominal or pelvic pain/cramping 7 (4%) 8 (9%) Urinary tract infection (UTI) 5 (3%) 3 (3%) Hot flashes 6 (3%) 3 (3%) Vaginal infection 2 (1%) 1 (1%) Nausea/vomiting 2 (1%) 2 (2%) 3

4 Table 1c -- Adverse Events at 3, 6, and 12 months Post-Procedure* Adverse Event Cryoablation n=186 REA n=86 Uterine cramping 7 (4%) 5 (6%) Other abdominal or pelvic pain/cramping 26 (14%) 16 (19%) Vaginal infection 7 (4%) 1 (1%) Hot flashes 3 (2%) 7 (8%) Urinary tract infection 2 (1%) 3 (3%) Nausea/vomiting 1 (.5%) 1 (1%) *Below is a more detailed description of the Adverse Events reported above: Pelvic Pain/Cramping Peri-operative cramping typically lasted a few hours and rarely continued beyond the first day following ablation. Some of the mild cramping was reported as resolved without medication. The use of non-steroidal anti-inflammatory drugs (NSAID s) was reported to typically manage the cramping and pain. Nausea and Vomiting Nausea and vomiting was managed with medication. Bladder Infection/Vaginal Infection The infections were managed with oral antibiotics. Other Events Other Adverse Events reported which occurred in no greater than 1% of the patients treated with Her Option include: severe bleeding (more than two weeks following the procedure), difficulty recovering from anesthesia and pregnancy (1 patient). Her Option was evaluated using an Extended Treatment Regimen (consisting of three potential freeze times of up to 10 minutes and a midline fundal freeze of 4 minutes or less) and the results were compared to the outcomes reported in the original PMA trial (using a 4 minute/6 minute treatment regiment). No serious intraoperative device-related adverse events were reported in the Extended Treatment Regimen group. Tables 2a - 2c summarize the adverse events for the 82 patients treated in this study: Table 2a - Adverse Events 24 Hours Post-procedure Event Description n=82 Pain/Discomfort Pelvic/Abdominal 3 ( 3.6%) Allergic Reaction/Hypersensitivity Reaction 2 ( 2.4%) Diarrhea 1 ( 1.2%) Headache 1 ( 1.2%) Hot Flashes 1 ( 1.2%) Menometrorrhagia 1 ( 1.2%) Pain/Discomfort Other 1 ( 1.2%) Table 2b - Adverse Events > 24 Hours to 2 Weeks Post-procedure Event Description n=82 Urinary tract Infection (UTI) 4 ( 4.9%) Endometritis 3 ( 3.7%) Abdominal Bloating/Gas 1 ( 1.2%) Dysuria 1 ( 1.2%) Hematuria 1 ( 1.2%) Fluid Pocket in Uterus Noted on Ultrasound 1 ( 1.2%) Pain/Discomfort Pelvic 1 ( 1.2%) 4

5 Table 2c - Averse Events at > 2 Weeks to 12 Months Post-procedure Event Description n=82 Infection Vaginal 3 ( 3.7%) Pain/Discomfort Pelvic 3 ( 3.7%) Hematometria 2 ( 2.4%) Abdominal Bloating/Gas 1 ( 1.2%) Dysmenorrhea 1 ( 1.2%) Endometrial Polyp 1 ( 1.2%) Non-menstrual Vaginal Bleeding with Lifting x 1 1 ( 1.2%) Pain/Discomfort Other 1 ( 1.2%) Premenstrual Syndrome (PMS) 1 ( 1.2%) Sexual Dysfunction (decreased libido) 1 ( 1.2%) Vaginal Discharge 1 ( 1.2%) Two serious device-related adverse events were reported during follow-up; one report of acute cystitis requiring IV antibiotics and one report of cervical stenosis resulting in hematometria. Below is a description of the two serious device-related adverse events reported in the study: One subject, experiencing abdominal pain, went to her local emergency room. Acute cystitis was diagnosed and the subject was admitted for observation and administration of IV antibiotics. The subject responded to medication well and was discharged with oral antibiotics. One subject presented for her 6-month follow-up visit with an enlarged uterus and accumulation of fluid in the endometrial cavity noted on ultrasound. Cervical dilation was performed to drain the accumulated menstrual discharge with no complications; however, she continued to experience hematometria due to cervical stenosis during her next several menstrual cycles and subsequently underwent hysterectomy. Potential Adverse Events: As with all endometrial ablation procedures, serious injury or death can occur. The following adverse events could occur or have been reported in association with the use of Her Option : Uterine cramping/pain Nausea/Vomiting Other abdominal or pelvic cramping/pain Vaginal infection Hot flashes Endometritis Difficulty with defecation or micturation Hematometra Thermal injury to adjacent tissue Hemorrhage Post ablation tubal sterilization syndrome Perforation of Uterus Complications with pregnancy (Note: Pregnancy following any endometrial ablation procedure is dangerous to both the mother and the fetus.) Uterine necrosis Infection or sepsis Complications leading to serious injury or death Clinical Study: Purpose: Her Option was evaluated in a randomized, prospective multi-center clinical study, comparing Her Option to a control arm of roller ball endometrial ablation (REA). The use of Cryoablation in the treatment of menorrhagia from benign causes in pre-menopausal women was compared to REA to evaluate safety and effectiveness. Study Endpoints: The primary effectiveness measure was a validated menstrual diary scoring system developed by Higham JM, O Brien PMS, Shaw RW. Assessment of menstrual blood loss using a pictorial chart (Br J Obstet Gynaecol 1990;97:734-9). Patient success was defined as a reduction in menstrual flow at 1 year to a diary score of <75. Study success was defined as a statistical difference of less than 20% in patient success rates between Cryoablation and REA. Secondary endpoints included responses from a quality-of-life questionnaire. Safety evaluation was based on the adverse events reported during the study, including device-related complications. The type of anesthesia required to complete the procedure was also recorded. 5

6 Methods: A randomized (2:1), prospective study was conducted at 10 clinical sites which included 275 patients diagnosed with menorrhagia. Study subjects were required to meet the following key inclusion/exclusion criteria Inclusion criteria: Premenopausal female, between 30 and 50 years of age, in good general health Documented history of excessive uterine bleeding and a completed pictorial blood assessment chart (PBAC) of >150 for at least one menstrual cycle Previously failed or refused traditional medical therapy, D&C and Depo-Provera Uterine sound measurement < 10 cm Uterine volumetric measurement < 300 cc. Exclusion criteria: Clotting defects or bleeding disorders Poor general health Patient below age 30 or above age 50 Active pelvic inflammatory disease Abnormal pap smear within the previous year, unless appropriately evaluated History of gynecologic malignancy within the past 5 years Intramural myomas greater than 2 cm diameter Intrauterine polyps Pedunculated fibroids Septate uterus Previous endometrial ablation procedure or other uterine surgery in which thinning of the uterine musculature occurs Malignant pathology or hyperplasia within the previous six months, as documented by endometrial biopsy Pregnancy Women who desire to maintain fertility Menstrual diary scores were collected pre-treatment and at 3, 6 and 12 months post-treatment. Patients were given Lupron (3.75mg) 28 days prior to the Cryoablation Therapy. Patient Population: A total of 279 patients were enrolled in this study in a 2:1 ratio of Cryoablation to Rollerball respectively. Baseline characteristics between Cryoablation and REA patients were compared and found to be statistically equivalent with regard to age, body mass index, gravidity, parity, full-term deliveries, previous Cesarean section, previous D&C, previous tubal ligation, presence of fibroids or myomas, cavity sounding length, severe menstrual pain and cramping, severe PMS symptoms, medical therapy for menorrhagia, hematocrit and FSH. One variable, pretreatment PBAC diary scores demonstrated moderate statistical significance (p<0.05). Median pretreatment PBAC scores were higher in the group treated with Cryoablation. Table 3: Subject Accountability Cryoablation REA TOTAL Intent to Treat Population Subject Withdrawals Complications/Incomplete Treatment Complete Treatments Subjects not available at 12 Month Follow-up Lost to follow-up Hysterectomy Repeat Ablation Population with 12-Month Data Available Subjects not available at 24 Month Follow-up Lost to follow-up Hysterectomy Population with 24-Month Data Available Subjects not available at 36 Month Follow-up Lost to follow-up Hysterectomy Subjects Lost to Follow-up at 24 months, returned at 36 Months Population with 36-Month Data Available

7 Results: Primary Effectiveness Endpoint Patient success was based on a reduction in excessive uterine bleeding to normal levels or better. A success at 12-months post procedure is defined as a reduction in diary scores from > 150 pre-treatment to < 75. Amenorrhea is defined as a score of 0. Success at 24 and 36 months is defined as Amenorrhea (no bleeding), Hypomenorrhea (light bleeding), or Eumenorrhea (normal menstrual bleeding) as reported by subject via questionnaire. Results at 12, 24 and 36-months post-treatment are presented below for the Intent to Treat (ITT) Population. Table 4: Effectiveness: Bleeding Rates for the Intent to Treat Population Intent to Treat Population: N = 279 Cryoablation n = 193 REA n = 86 Months post treatment 12 a 24 b 36 b 12 a 24 b 36 b Number of successful subjects Study success rate 67% 31% 39% 73% 34% 34% Number of subjects with Amenorrhea Amenorrhea rate 22% 8% 11% 47% 20% 20% Intent to Treatment (ITT) population represents all subjects enrolled in the study including those considered as failures because they were not available for follow-up, did not receive treatment, and/or received partial treatment. Therefore, the ITT group represents a worse case scenario for effectiveness. See Subject Accountability section for complete accounting of all subjects enrolled in the study. a Based on diary score. b Based on questionnaire response. Secondary Effectiveness Endpoint Quality of Life (QOL) information was obtained by comparing QOL scores obtained via questionnaire at pretreatment and at 12, 24, and 36 months post-treatment. These scores were compared and the results are presented below. Quality of Life (QOL) data was obtained at one year post-operatively using the SF-36 Health Survey as well as a version of the validated Dartmouth COOP assessment tool. Because there are no QOL questions pertaining to menorrhagia, approval from the Dartmouth Committee was granted to use the same style of questions and format them according to the study design. Parameters included SF-36 PMS symptoms and menstrual pain indices. A telephone survey was also conducted at 2 and 3-years post-operatively. Table 5 summarizes QOL responses to the survey. Table 5: Quality of Life (QoL) Scores Out to 3 Years Post-Treatment Effect on QoL* (1=Not at all, 5=Extremely) Pre-operatively (CRYO=180, REA=82) 1 Year (CRYO=157, REA=73) 2 Years (CRYO=72, REA=25) 3 Years (CRYO=75, REA=22) Percentage of subjects reported time lost from work/other activities* Pre-operatively (CRYO=180, REA=82) 1 Year (CRYO=157, REA=73) 2 Years (CRYO=74, REA=25) 3 Years (CRYO=76, REA=22) Percentage of subjects very/extremely satisfied** 1 Year (CRYO=157, REA=73) 2 Years (CRYO=90, REA=36) 3 Years (CRYO=103, REA=38) Percentage of subjects who would recommend therapy to a friend** 1 Year (CRYO=157, REA=73) 2 Years (CRYO=89, REA=36) 3 Years (CRYO=102, REA=37) CRYO % 6% 8% 8% 86% 90% 89% 96% 97% 97% REA % 7% 8% 9% 88% 86% 82% 94% 94% 97% * Responses include only subjects experiencing menstruation or symptoms. Those not menstruating or experiencing symptoms did not complete this section of the questionnaire. **Responses were not recorded for all subjects. 7

8 Anesthesia and Dilation Anesthesia was delivered at the discretion of the investigator and attending anesthesiologist. General anesthesia was administered to 92% (79/86) of the REA patients and 46% (85/186) of the Cryoablation patients. Of the Cryoablation group, 39% (72/186) of the patients received a paracervical block with conscious sedation as compared to only 1% (1/86) of the REA group. There are data specific to the degree of dilation available on 164 Cryoablation patients and 76 REA patients. Of these patients, twenty-one (11%) of the Cryoablation patients did not receive any dilation, whereas all (100%) REA patients received some degree of dilation. This difference is statistically significant with a p value of Clinical Study Observations Hysterectomy There were a total of 28 patients (16 Cryoablation; 12 REA) who had hysterectomies within 3 years following endometrial ablation. Table 6: Summary of Reasons for Hysterectomy within 3 years Reason for Hysterectomy Cryoablation Menorraghia/Abnormal Uterine Bleeding (n=193) REA (n=86) 10 6 Unreported/Unknown 4 1 Pain/Fibroids 2 2 Ovarian Cyst 0 1 Ovarian Cancer 0 1 Severe PMS 0 1 Total Ten Hysterectomies were in patients <40 years (6 Cryoablation; 4 REA); 18 hysterectomies were in patients >40 years (10 Cryoablation; 8 REA) based on age at the time of the Cryoablation Therapy Post Market Clinical Study: Purpose: American Medical Systems, Inc. (AMS) conducted an Extended Treatment Regimen using Her Option to compare outcomes from the original PMA trial, using a 4 minute/6 minute treatment regimen, with an extended treatment regimen consisting of three potential freeze times of up to 10 minutes each and a midline fundal freeze of 4 minutes or less. Study Endpoints: The primary endpoint of the study was to assess reduction of menstruation to normal or less as defined by a pictorial bleeding assessment chart (PBAC) score of 75 at 1-year post-treatment and compare results to the original PMA study. Safety was assessed by monitoring the occurrence of side effects and/or complications associated with the study treatment. Secondary objectives included evaluation of the efficacy of the study treatment in relieving pain/discomfort attributed to abnormal uterine bleeding (AUB) and improving quality of life. Efficacy was evaluated using a validated Pictorial Bleeding Assessment Chart (PBAC) 1. Quality of life measures were captured using a standardized questionnaire. Methods: Eighty-two patients were treated within this 7-site study, and have completed the 12-month follow-up point. The number of freezes and position of the Cryoprobe for each of the freeze cycles was determined by the uterine dimensions. Treatment Regimen: Uterine cavities were assessed using transvaginal and transabdominal ultrasound. Measurement of intra-cornual distance and uterine cavity length were obtained. For uterine cavities with 1 Higham JM, O Brien PMS, Shaw RW. Assessment of menstrual blood loss using a pictorial chart. British Journal of Obstetrics and Gynecology, 1990:97:

9 a width 2 cm, two freeze cycles were performed at the level of the fundus, one freeze at each cornu. For uterine cavities > 2 cm at the fundus, three freezes were performed; a midline fundal freeze and one in each cornu. For uterine cavities (not including the cervical length) lengths 5 cm, an additional freeze was performed with the Cryoprobe tip at midline and pulled back from the fundus. The pullback distance equaled the uterine length minus 4.5 cm. All freeze cycles were monitored on ultrasound and were terminated if the leading edge of the CryoZone was determined to be within 2 mm of the uterine serosa. Midline fundal freeze cycles were limited to a maximum of four minutes in duration and freeze durations in the cornua were limited to a maximum of 10 minutes in duration. Freeze durations in the cornua or in the body of the uterus (referred to as a pullback freeze) varied based on the thickness of the myometrium, but were terminated at 10 minutes. Table 7 summarizes the freeze regimens used during the study procedure. Table 7 - Summary of Potential Freeze Patterns Uterine Length 1 Uterine Width at Fundus 2 cm > 2 cm < 5 cm 1) Cornual freezes bilaterally 1) Midline fundal freeze 4 min. 2) Cornual freezes bilaterally 5 cm 1) Cornual freezes bilaterally 2) Pullback freeze (uterine length 4.5 cm) 1) Midline fundal freeze 4 min. 2) Cornual freezes bilaterally 3) Pullback freeze (uterine length 4.5 cm) 1 Uterine length = Uterine sound minus cervical length Inclusion/Exclusion Criteria: Inclusion Criteria: Subjects were considered eligible for continued inclusion in the study if they met all of the following qualifications: Premenopausal adult women 30 years of age Menorrhagia secondary to dysfunctional uterine bleeding (DUB) as determined by a pictorial bleeding assessment chart (PBAC score > 150) Refractory to failed medical therapy Uterine sound measurements: 4 10 cm Willing and able to complete all follow-up exams as required by protocol Exclusion Criteria: Subjects were excluded from the study if any of the following conditions were present: Known or suspected endometrial carcinoma or premalignant change of the endometrium such as unresolved adenomatous hyperplasia Untreated cervical dysplasia Hereditary malformations of the uterine cavity (e.g., T-shaped, unicornuate, septate) or other distortion of the cavity that would prevent insertion and/or placement of the Cryoprobe Myoma(s) 3 cm in diameter History of invasive treatment for AUB or uterine myomas History of classical cesarean section Active genital or urinary tract infection Acute pelvic inflammatory disease (PID) Intrauterine device (IUD) in place Pregnancy Desire to maintain fertility Patient Population: A total of 82 subjects were enrolled in this study at 7 sites. Baseline characteristics between the original Cryoablation PMA cohort and the extended treatment regiments cohort were compared and found to be statistically equivalent with regard to age, body mass index, gravidity, parity, full-term deliveries, previous Cesarean section, previous D&C, previous tubal ligation, cavity sounding length, severe menstrual pain and cramping, severe PMS symptoms, medical therapy for menorrhagia, hematocrit and FSH. Two variables, pretreatment PBAC diary scores and presence of uterine fibroids, were noted to be statistically different between 9

10 the groups. Pretreatment PBAC diary scores were statistically higher in the original PMA study, and the extended treatment regimens cohort had a higher incidence of uterine fibroids due to the inclusion of myomas up to 3 cm as compared to up to 2 cm in the original trial. Table 8: Subject Accountability Consented and Enrolled 107 Did not meet Study Inc/Exc Criteria -18 Withdrew Consent -5 Change in Medical Condition -2 Complete Treatments 82 Subjects not available at 12 Month Follow-up Lost to follow-up -7 Alternative Treatment -4 Exited Due to Adverse Event -2 Missed Visit -1 Population with 12-Month Data Available 68 Results: Primary Effectiveness Endpoint The safety and effectiveness of an Extended Treatment Regimen (ETR) consisting of additional freeze locations and a maximum freeze time of 34 minutes were evaluated in a small series of patients (N=82) with menorrhagia. Both the original Her Option treatment regimen (i.e. bilateral cornual freeze with maximum total freeze time of 10 minutes) and the ETR have been shown to be effective in reducing menorrhagia. Patient outcomes (i.e. bleeding scores) following Her Option ETR were not significantly better compared to subjects in the pivotal clinical trial of Her Option who received the original treatment regimen. The ETR did not increase the risk of adverse events, compared to the original treatment regimen with the possible exception of slightly increased risk of hematometra. While shorter treatment times are an advantage for both patient and physician, it is possible that some patients may benefit from altering the treatment regimen, particularly those patients with uterine sound lengths at or above 9 cm or uterine width at the fundus, which would potentially leave the midline fundal region untreated 2,3. With appropriate cavity assessment of the patient s specific anatomy prior to treatment and use of real-time ultrasound to monitor location and progression of the CryoZone, freeze cycles of up to 10 minutes, with a total potential treatment time of up to 34 minutes, were well tolerated, and no adverse events relating to freezing through to adjacent organs were reported. Table 9: Effectiveness: Bleeding Rates (Fibroid Analysis) for the Intent to Treat Population Extended Freeze n=82 Number of successful subjects 59 Study success rate 72.0% Number of subjects with amenorrhea 15 Amenorrhea rate 18.3% Patients with fibroids 35 Successful patients 27 Success rate fibroids 77.1% Patients without fibroids 47 Successful patients 32 Success rate no fibroids 68.1% 2 Bruno, R., McLellan, R., Herd, JK. Factors affecting outcomes in cryoablation. J Am Assoc. Gynecol. Lap. 2003, Nov., p. S16. 3 Weather Jr, L. Endometrial cryoablation with adjustment for intracavitory length. J Am Assoc. Gynecol. Lap. 2003, Nov., p. S16. 10

11 Secondary Effectiveness Endpoints Assessment of Reduction of Pain/Discomfort Attributed to AUB: Reduction of pain/cramping and PMS symptoms were assessed prior to and following treatment. Marked reduction of symptoms following treatment was noted in both categories. Table 10: Reduction of Pain/Discomfort due to AUB Baseline (n=82) 12-Month (n=66) 1 Pain/Cramping (moderate to severe) 71 (87%) 14 (21%) PMS symptoms (moderate to severe) 70 (85%) 10 (15%) 1 Two subjects ( and ) were evaluated but did not completed the QOL CRF Assessment of Improvement in Quality of Life Moderate to extreme impact of menstrual bleeding on quality of life and incidences of bleeding through onto clothing was reported by 95% of subjects at the baseline assessment. At the 12 month visit, only 8% of subjects reported negative impact on quality of life, and bleed-through incidences were reduced to 23% of subjects. Satisfaction with outcome was high, and most subjects would be willing to recommend Her Option procedure to a friend. Table 11: Secondary Outcomes Relating to Symptoms/QOL Baseline 12-Month Affect on QOL (moderate to extreme) 78/82 (95%) 5/66 (8%) 1 Bleeding through onto clothing 77/81 (95%) 2 15/65 (23%) 1, 2 Perceived eumenorrhea or less NA 64/65 (99%) 1, 2 Satisfaction (moderate to extreme) NA 59/64 (92%) 1, 2 Recommend procedure to a friend NA 61/64 (95%) 1, 2 1 Two subjects ( and ) were evaluated but did not completed the QOL CRF 2 Some subjects completed the QOL CRF however did not completely answer all the questions. Safety Endpoint The safety of extended treatment regimens of up to 34 minutes was demonstrated to be acceptable both within the office setting and surgical center. Intra-operative and acute post-operative uterine and abdominal pain/cramping was addressed successfully without any IV access in 65/82 (79%) of subjects, with the remainder receiving IV sedation as standard-of-care at two institutions. In order to assess tolerability for longer treatment regimens, pain scale scores were analyzed after each treatment cycle. Table 12 summarizes pain scale scores following each freeze cycle. Pain scores remain similar across cycles. Table 12: Mean Intra-procedural Pain Scale Scores by Freeze Cycle Freeze Cycle n 1,2 Mean SD 1 st Freeze Cycle nd Freeze Cycle rd Freeze Cycle th Freeze Cycle Procedure pain scale scores were not obtained for two subjects due to I.V. sedation levels. 2 Pain scores for freeze cycle three were missed for subjects and Clinical Study Observations Retreatment for AUB: Four subjects elected to undergo additional treatment for abnormal uterine bleeding. Of the four subjects, one successfully underwent repeat Her Option Endometrial Cryoablation, one subject underwent transcervical resection of the endometrium (TCRE), one subject underwent rollerball endometrial ablation (REA), and one subject elected hysterectomy. 11

12 Patient Selection: Menorrhagia can be caused by a variety of underlying problems including, but not limited to, endometrial cancer, hormone imbalance, anovulation, drugs, myomas and polyps. Patients should be thoroughly evaluated to determine the cause of the menorrhagia prior to any treatment being initiated. Patient Selection for Office Based Procedures: Patients with the following conditions may not be appropriate candidates for office based procedures: Patients who have uncontrolled anxiety, pain, or moderate systemic diseases (such as hypertension, arrhythmias, arteriosclerotic vascular disease, severe obstructive lung disease) Patients who have a difficult anatomy which impedes ultrasound visualization. Patient Information: Patients should be counseled regarding the risks, benefits and alternatives prior to the performance of this procedure. This counseling should include the need for post-procedure contraception where indicated. This procedure is not a sterilization procedure and subsequent pregnancies may be dangerous for the mother and fetus. Vaginal discharge is possible following the procedure. This may last from a few days to a few weeks. Any unusual or foul smelling draining should be reported to the physician immediately. Pre-Op Work Up: The Pre-op work up should include: History and complete physical examination, including pelvic exam; negative PAP smear and endometrial biopsy to rule out cervical or endometrial malignancy and premalignant changes to the uterus; sonography, hysteroscopy, hystero-salpingography or any other indicated diagnostic test or procedure that might uncover a possible cause for menorrhagia within six months of performing Her Option procedure. Assessment of the uterine cavity to determine appropriate freeze regimen should be done at this time. Pre-Treatment Preparation of Patient: It is recommended that the lining of the uterine cavity be thinned prior to Her Option. Thinning can be accomplished by administering a GnRH agonist days prior to the procedure or performing suction curretage immediately prior to the Cryoablation procedure. A non-steroidal antiinflammatory drug (NSAID) may be given to the patient one hour prior to the treatment and continued postoperatively as needed. Clinical Use Checklist: Prior to using Her Option for the first time, physicians should be trained and familiar with the following procedures and techniques: Intrauterine gynecological procedures; Recognizing the tip of the Cryoprobe in the uterus and the CryoZone as it advances toward the serosa; Placing the tip of the Cryoprobe in the uterine cornu; Confirming (via ultrasound) maintenance of the proper placement of the Cryoprobe tip and Cryoablation of the cervix Office Based As is the case with office based procedures such as endometrial biopsy, loop electrosurgical excision procedure [LEEP], hysteroscopy and endometrial ablation, physicians that perform HerOption should follow these general recommendations: Vasovagal effects can occur with any manipulation of the cervix. Office personnel should be trained in airway management, with advanced cardiac life support. Prepare an emergency kit with appropriate pharmacological agents to assist in managing emergency situations; be prepared to check blood pressure and provide hemostasis for cervical lacerations. Know your local anesthetic s maximum dose. To avoid the risk of overdose draw out the maximum dosage. Overdose symptoms include: dizziness, lightheadedness, tinnitus, depression, and systole. In case of severe reaction be prepared to administer appropriate pharmacological agents. The physician, as well as adjunctive personnel, should review and be familiar with Her Option training material (User s Manual, training video, Clinical Use protocol). 12

13 Power Source: Specification 100/120/220/240 VRMS 50/60 Hz 1200 VA Voltages Frequency Rating PROBE (CRYOPROBE WITH A DISPOSABLE PROBE) (+) Heat Button (Amber Light) (-) Freeze Button (Green Light) Keypad Handle Probe (5.5 mm x 22 cm) Locking Tabs Irrigation Port Tip with Thermocouple and Heater Injection Port Physician Preparation: Physician preparation for procedure is dictated by the site of service (i.e., office setting, ASC, operating room, etc.) and local practice standard. Site Preparation: Patient is placed in dorsal lithotomy position. Physician prepares perineum, vagina and cervix with antiseptic solution per local practice. Physician uses sterile drape exposing perineum only. Physician conducts pelvic examination to determine size, shape and position of cervix and uterus. Physician sounds cervix and uterus. Physician employs speculum and/or retractors, and sufficient illumination so as to provide adequate visualization of the cervix. Directions For Use: The following directions provide some of the salient points for the use of Her Option. Please read the User s Manual before operating the system. The use of Her Option requires two people, a non-sterile Assistant and a sterile-gloved Physician. The Console display provides information that will help guide you during the procedure pay attention to the screen display. The sterile Disposable Probe should always be handled using sterile technique. To attach the Disposable Probe to the Cryoprobe, use a slow steady motion and gently push the Disposable Probe until the locking tabs are fully engaged into the Cryoprobe handle. 13

14 A PreCool Cycle must be performed immediately prior to use. The PreCool Cycle will last approximately 2-5 minutes and the heating portion ends when the heater automatically warms up to 37C. Begin the first freeze within 60 minutes of the PreCool Cycle, otherwise, the PreCool Cycle may have to be repeated. The user will be prompted if a Precool is necessary. The Precool Cycle should be performed with the Probe outside the patient s uterus. Caution: It is very important that the PreCool cycle be conducted with the Disposable Probe that will be used for the treatment. Test Probes should not be used for PreCool cycle. You may need to dilate the cervix to 6mm. For optimal image when using ultrasound guidance in positioning the Probe, the bladder should be full to ensure adequate ultrasound imaging. 5-10cc of saline injected into the uterus eliminates air pockets and will ensure good thermal contact between the Probe and the tissue. The first freeze cycle should be terminated by depressing the Heat (+) button after 4 minutes, or earlier if ultrasound imaging indicates that the CryoZone leading edge approaches 2mm of the serosal surface of the uterus. At the completion of the heat cycle, inject 5-10cc of saline and reposition towards the opposite lateral cornu. Verify correct placement with ultrasound. If Probe resistance is encountered during the second placement, inject warm saline to expedite the thawing process of initial CryoZone. Confirm appropriate placement by injecting saline in the uterine cavity and identifying the flow of saline using ultrasound guidance. In addition, ultrasound visualization can be used to verify that the placement of the Probe is out of the first CryoZone by visualizing the tip while sliding the Probe in and out for approximately 1 cm. The second freeze should last for only 6 minutes, or less if the CryoZone leading edge approaches 2mm of the serosal surface. Note: The Probe should only be withdrawn from the CryoZone when the registered tip temperature is above 20C. 14

15 CryoZone Dimensions: 2 minute freeze 4 minute freeze 6 minute freeze 5.0 cm 5.4 cm 5.8 cm 2.0 cm 2.6 cm 3.0 cm 8 minute freeze 10 minute freeze 3.3 cm 6.1 cm 6.7 cm 3.3 cm 3.6 cm *The CryoZone dimensions illustrated above were obtained during in-vitro testing in media that simulates tissue. Please note that the illustrations above represent the growth of the CryoZone over a period of time. Ultrasound provides visualization of the CryoZone and the proximity of the leading edge to the serosal surface of the uterus. (ETR 04060) Article Reference: Levy, Barbara A., Isaacson, Keith. Office-based treatment of abnormal uterine bleeding; OBG Management. September

16 For Immediate Technical Support, Call: (800) Explanation of Symbols Reorder number Do not use if package is damaged or opened. Batch code Do not re-sterilize Use-by date Do not re-use Sterilized using irradiation Caution: U.S. Federal law restricts this device to sale by or on the order of a physician. Consult instructions for use Not made with natural rubber latex Caution Date of manufacture Manufacturer Her Option is a registered trademark of CooperSurgical, Inc. CooperSurgical is a registered trademark of CooperSurgical, Inc CooperSurgical, Inc. CooperSurgical, Inc. 95 Corporate Drive Trumbull, CT USA Made in the USA 95 Corporate Drive Trumbull, CT USA Phone: (800) Fax: (800) Rev. N 2/15 16