ࡱ>  dbjbjVV h<<!' ''DEt$2$(%:?%?%?%&&&A9.&&..'6]?%?%ɲJJJ.18?%?%J.JJȤiĬ?%b/2h>Lz߲0ԧ} C}Ĭ}Ҭ&(J*,,&&&I`&&&....}&&&&&&&&& : VA/DoD Drug Class Review: Luteinizing Hormone Releasing Hormone (LHRH) Agonists in Prostate Cancer Update November 2007 and June 2010 Department of Defense Pharmacoeconomic Center (DoD PEC) Department of Veterans Affairs Pharmacy Benefits Management Service (VA PBM) and the VA Medical Advisory Panel (VA MAP) Introduction The purpose of this review is to assess the efficacy, safety, and administration of the LHRH agonists currently available in 1, 3, 4, 6 or 12-month preparations for the treatment of prostate cancer. This review will also define selection criteria for contracting of these agents for the Veteran Health Administration (VHA). Table  SEQ Table \* ARABIC 1: LHRH agonists available in the U.S for treatment of prostate cancer Generic Brand (Manufacturer)Strength & FormulationFDA approval date & earliest patent expirationGoserelinZoladex (Astra-Zeneca)3.6mg implant 10.8mg implant1989 2011 1996 2011HistrelinVantas (Indevus)50mg implant2004 2010LeuprolideEligard (Sanofi-Aventis) Lupron (TAP) Viadur (Bayer)7.5mg injectable suspension 22.5mg injectable suspension 30mg injectable suspension 45mg injectable suspension 7.5mg depot suspension 22.5mg depot suspension 30mg depot suspension 65mg implant2002 2008 2002 2008 2003 2008 2004 2008 1989 2013 1995 2013 1997 2013 2000 2017TriptorelinTrelstar (Watson)3.75mg injectable suspension 11.25mg injectable suspension 22.5mg injectable suspension2000 2010 2001 2010 2010Nafarelin (Synarel) Nasal Solution not included because is does not have an indication for prostate cancer. Prostate cancer is the most frequently diagnosed cancer; one in eight men will be diagnosed during his lifetime. Annually, greater than 200,000 are diagnosed and 27,000 die from their disease making it the second leading cause of cancer death in American men. In the VHA in 2005 there were 10,530 new cases diagnosed. Prostate cancer has been detected at an increasing frequency in the United States and other Western countries, primarily driven by the increased number of prostate biopsies performed in asymptomatic men due to an elevated prostate specific antigen (PSA). Wide variations in biopsy rates between countries contribute to substantial differences in incidence rates. Important risk factors include age, ethnicity, genetic factors, and possibly dietary factors. Prostate cancer is rare before the age of 40 but the incidence then increases rapidly. It is more common in African-Americans than in whites or Hispanics and the age of onset is earlier. Finally, the risk is elevated two-fold in men with an affected first degree relative (father, brother), with a trend towards increased risk with a greater number of affected family members. This review will focus on the use of LHRH agonists in prostate cancer. Another review will focus on the use of these agents in women. Pediatric use for precocious puberty will not be addressed. FDA-Approved Indications and Off-Label Uses Table 2: FDA indications for LHRH agonist therapy IndicationDrugLeuprolide Depot (Lupron)Leuprolide Atrogel (Eligard)Goserelin (Zoladex)Triptorelen (Trelstar)Leuprolide Implant (Viadur)Histrelin Implant (Vantas)Prostate CarcinomaYesYesYesYesYesYesBreast CancerOff-labelYesOvarian CancerOff-labelOff-labelEndometriosisYesYesEndometrial Thinning (DUB)YesUterine LeiomyomataYesOff-labelOff-labelCentral Precocious PubertyYesYes (SupprelinLA) Methods 1. Included in this review were all LHRH agonists with an FDA indication for the treatment of advanced prostate cancer. 2. A PubMed search was conducted for the time period 2002-2007 coinciding with the years since the last drug class review. Randomized Clinical Trials were searched using the following terms: goserelin, leuprolide, Eligard, Viadur, histrelin, triptorelin, LHRH agonists, and prostate cancer. Systematic reviews were searched using the following terms: goserelin, leuprolide, histrelin, triptorelin, LHRH agonists, and GnRH agonists. Clinical trials were limited to major comparative trials. Use in combined androgen blockade and as adjuvant therapy with radiation was reviewed for completeness, but data are presented for descriptive purposes only. 3. A search of three evidence based medicine databases (Cochrane, ACP Journal Club, and Database of Abstracts of Reviews of Effects yielded one Cochrane Review on the use of LHRH agonists for adjuvant and neoadjuvant treatment of localized and locally advanced prostate cancer. 4. An on-line evidence based medicine source, UpToDate, was searched using the term prostate cancer. Pharmacology LHRH agonist analogues suppress endogenous testicular gonadotropin synthesis, causing a hypogonadal condition. Chronic administration of LHRH agonists exerts constant stimulation on the pituitary gland, causing desensitization and down-regulation of pituitary LHRH receptors leading to suppression of Luteinizing Hormone and Follicle Stimulating Hormone levels. In men, testosterone levels diminish to castrate levels within 14-28 days of therapy, and reverse upon discontinuation. A transient stimulatory phase of 1-2 weeks occurs due to elevated testosterone and dihydrotestosterone levels. At this point in therapy, 4-63% (mean 11%) of patients experiences a flaring of disease symptoms (see safety). Pharmacokinetics Table 3: Pharmacokinetic properties,,,,, DrugTime to Peak Plasma levelOnset of Steady State LevelT1/2VdProtein BindingMetabolismExcretionHepatic/Renal ImpairmentGoserelin12-15d(3.6mg) 4.2h44L27.3%hydrolysis90+% renal HepaticCLCR<20ml/min !t, !CL=no change in dose Hepatic: no change in doseHistrelin implant*12 h3.92h58.4L70.5%Hydrolysis, deacetylationNot studiedCLCR 15-60= !50% serum levels; not clinically significant Hepatic: not studiedLeuprolide Depot4 hours3h27L43-49%To smaller inactive peptides<5% of parent and major metabolite recovered in urineNot determinedLeuprolide Suspension3.3-5h3h27L43-49%Not studiedNot studiedNot determinedLeuprolide Implant**3 h27LNot studiedNot studiedNot studiedTriptorelin suspension1-3h(3.75mg)3h30-33L0%Unknown, but likely CYP450; no metabolites identifiedRenal(41.7-62.3%) and HepaticT1/2=7.65h (severe renal impairment) T1/2=7.58h (liver disease)CLCR=creatinine clearance *Histrelin implant is a non-biodegradable, diffusion-controlled reservoir drug delivery system that delivers drug continuously over 12 months. ** Leuprolide implant is a non-biodegradable, osmotically drive implant that delivers drug at a controlled rate over 12 months Dosing and Administration Table 4: Dosing and administration DrugPreparation and AdministrationGoserelin 3.6mg Subcutaneously every 28 days Goserelin 10.8mg Subcutaneously every 3 months (Implant is a biodegradable copolymer matrix)Administer into upper abdomen Needle is tunneled parallel to the skin and fat When the hub touches the skin, the needle is pulled back 1 cm to insert the pellet 3.6mg dose has 16g needle with SafeSystemTM 10.8mg dose has 14g needle with SafeSystemTMHistrelin Implant 50mg every 12 months (Implant is a non-biodegradable diffusion-controlled hydrogel reservoir)Sterile technique and sterile gloves required to minimize infection risk Patient flexes arm while lying down allowing access to inner aspect of upper arm Load the insertion tool Swab arm with betadine, drape, and inject local anesthetic Make a 2-3mm incision with scalpel, insert tip of insertion tool, release lock mechanism, palpate to check for implant; close incision with 1-2 sutures, apply antibiotic ointment and 2 surgical strips and cover with gauze dressing Must be surgically removed after 12 months A kit is provided with all materials neededLeuprolide Depot 7.5 mg intramuscularly every 28 days Leuprolide Depot 22.5 mg intramuscularly every 3 months Leuprolide Depot 30 mg intramuscularly every 4 months (Product is microspheres of drug incorporated into a biodegradable copolymer)Provided in a prefilled dual chamber syringe Syringe is activated by the plunger, mixing the diluent with the lyophilized microspheres and forming a suspension All syringes have a LuproLocTM safety needle Volume after reconstitution: 7.5mg-1.1ml, 22.5mg and 30mg-1.7mlLeuprolide Suspension 7.5 mg subcutaneously every 28 days Leuprolide Suspension22.5 mg subcutaneously every 3 months Leuprolide Suspension 30 mg subcutaneously every 4 months Leuprolide Suspension 45mg subcutaneously every 6 months (Drug is incorporated into a polymeric delivery system comprised of a biodegradable polymer dissolved in a compatible solvent [Atrigel Delivery System] that forms a solid drug delivery depot in vivo)Allow product to come to room temperature Connect the 2 syringes provided; inject the liquid contents into lyophilized powder syringe, mix thoroughly for 45 seconds by pushing contents back and forth between the 2 syringes Connect provided needle Administer subcutaneously in abdomen, upper buttocks, or anywhere with sufficient subcutaneous tissue Withdraw needle and gently massage areaLeuprolide Implant 65 mg every 12 months (Implant is a non-biodegradable osmotically driven miniaturized implant that delivers drug at a controlled rate over 12 months)In-office physician procedure Identification of the insertion site Load implant into implanter device Preparation of the sterile field Anesthetize the site Make incision and insert the implant; close with steri-strips Implant must be surgically removed after 12 months A kit is provided containing all materials for insertion & removalTriptorelin pamoate Depot 3.75 mg intramuscularly every 4 weeks Triptorelin pamoate LA 11.25mg intramuscularly every 12 weeks Triptorelin pamoate 22.5mg intramuscularly every 24 weeks (Drug is in a biodegradable microgranule formation for suspension)Reconstitute with sterile water for injection Also available as a Mixject single dose delivery system with pre-filled syringe containing sterile water Shake well to form uniform milky suspension Inject intramuscularly into either buttock Table 5: Storage and Handling DrugStorage and InstructionsGoserelinStore at Room TemperatureHistrelin implantStore at 2-8C, Protect from light, Do not FreezeLeuprolide DepotStore at Room Temperature Use immediately after reconstitution; suspension settles quicklyLeuprolide SuspensionStore at 2-8C; Allow to reach room temperature before use Once mixed, the product must be administered within 30 minutesLeuprolide ImplantStore at Room TemperatureTriptorelin Store at Room Temperature; Do Not Freeze Use immediately after reconstitution Efficacy The gold standard in hormonal manipulation to suppress plasma testosterone levels in advanced prostate cancer, established in 1941, is orchiectomy. This standard is based on pioneering work that established the androgen dependency of prostate carcinoma. Estrogen, primarily diethylstilbestrol (DES), has also been shown to effectively suppress testosterone to castrate levels. Several large studies, including the Veterans Administration Cooperative Urology Research Group (VACURG), compared DES to orchiectomy and found them to be equivalent., Trials with LHRH agonists compared to either orchiectomy, DES, or another LHRH agonist will be considered. Efficacy Measures Due to the large differences in the time span between clinical trials with older agents (e.g. Lupron) and newer agents (e.g. Eligard), the efficacy measures may not be exactly equivalent because of changing requirements by the FDA and advancements in science. 1. Objective Response and subjective response (change in bone pain) 2. Suppression of serum testosterone to castrate levels (<50ng/dL) and decrease in Prostatic Specific Antigen (PSA) or prostatic acid phosphatase 3. Timed Events: time to progression, time to treatment failure, overall survival 4. Quality of Life 5. Adverse Effects Efficacy Trials The clinical trials section will concentrate on randomized, controlled trials with an active comparator, either orchiectomy, DES, or another LHRH agonist. In addition, this review will concentrate on landmark studies and registration trials establishing efficacy of LHRH agonist monotherapy in the treatment of metastatic prostate cancer. Non-comparative registration trials will also be included when no comparative trials exist. Multimodality use of the agents in early disease will be briefly summarized. Table 6: Results of trials comparing LHRH agonists to orchiectomy or DES in metastatic prostate cancer Reference (trial design)Number of PatientsTrial Duration (wk)OutcomeResultsLeuprolide Study Group Leuprolide 1mg SC daily Vs DES 3mg orally daily19912-120Serum T DHT Prostatic Acid phosphatase Objective response Change in bone pain Time to Progression Overall survivalSerum T: No difference DHT: No difference Prostatic Acid Phosph: No difference Objective Response: No difference Bone pain: No difference TTP: No difference Overall survival: No differenceLeuprolide 1mg daily vs DES 3mg daily (includes Westside VA)2560Objective response Bone pain Obstructive symptoms Analgesic use Acid phosphatase Serum T DHTSerum T: No difference after wk 4 DHT: No difference after wk 4 Acid phosphatase: sample too small for statistical purpose Bone pain, other symptoms: No difference Objective response: No differenceLeuprolide Depot 7.5mg IM monthly vs Leuprolide 1mg SC daily5624-150Objective response Serum T Acid phosphatase LHSerum T: No difference LH: similar pattern to serum T Objective response: no difference Acid phosphatase: no differenceZoladex Prostate Study Group Zoladex 3.6mg SC every 28 days vs Orchiectomy283208Objective response Time to treatment failure Overall survival Serum T Acid phosphataseObjective Response: No difference Serum T: No difference by wk 4 Acid phosphatase: No difference TTF: No difference Overall survival: No differenceTriptorelin 3.75mg IM Q28 days vs Leuprolide 7.5mg IM Q28 days28436% serum T (Castration % maintenance of castrate T levels months 2-9 OS QoL PSA Bone pain% serum T (castrate level Day 29 : > in Leuprolide group Day 57: No difference OS at 9 months 97% in Triptorelin group 96.5% in Leuprolide group Bone Pain: No difference % maintained castrate levels months 2-9: No differenceNon-comparative trialsLeuprolide for injectable suspension 7.5mg Sc monthly12024Serum T (castrate levels x2)Serum T castrate level 17.6% by Day 14 94.1% by Day 28 100% by Day 42 (97.5% (20ng/dL)Leuprolide suspension 22.5mg LA-2250 Q3 months SC11724 (2 injections)Serum T (castrate levels x2)Serum T castrate level 20% by Day 14 99% by Day 28 100% by Day 35 100% at end of six months (94%(20ng/dL)Leuprolide suspension 30mg LA-2575 Q4 months SC9032 (2 injections)Serum T (castrate levels x2Serum T castrate level 20% by Day 14 81% by Day 21 94% by Day 28 100% by Day 42 (84% (20ng/dL)Leuprolide suspension 45mg LA-2585 Q6 months SC11152 (2 injections)Serum T (castrate levels x2Serum T castrate level 97% by Day 28 99% by Day 365 (88% (20ng/dL)Histrelin implant13460Serum T castration levels weeks 4-52Serum T castrate level 100% By week4 99% by week 52Histrelin implant 1 implant=15 2 implants=19 4 implants=842120Serum T castration levels weeks 4-52Serum T castrate level 100% by week4 100% at 6 months 100% at 12 months 100% at 18 months 100% at 24 months 100% at 30 months No difference between patients who received 1, 2, or 4 implants at each cycleLeuprolide Implant 1 implant =27 or 2 implants=24 Part A: weeks 1-52 Part B: weeks 53-605160Serum T castrate levelsSerum T reached castrate level in 100% between weeks 2-4 and continued until week 60; no increase in serum T when changing implants at week 52.Leuprolide Implant8060Serum T castrate levelsSerum T reached castrate level in 99% by week 4 and 100% through week 60Triptorelin22.5mg suspension12048Serum T castrate levels97.5% by day 29 93% maintained months 2-12 98.3% at end of study SC=subcutaneously, DES=diethylstilbestrol, Serum T=serum testosterone, DHT=dihydrotestosterone, IM=intramuscularly, ` LH=luteinizing hormone, Table 7: Comparison of Percentage Reaching Castrate Levels at Day 28-30 LHRH AgonistCastrate percentageGoserelin ImplantNRHistrelin Implant100Leuprolide Depot94-95Leuprolide Suspension94-99Leuprolide Implant99Triptorelin Suspension91.2-97.7 Table 8: Results of LHRH agonist trials in multimodality treatment Reference (trial design)ResultsMaximal Androgen Blockade for Advanced DiseaseCochrane Review Prostate Cancer Trialists Collaborative Group PCTCG Samson, et al. Klotz, et al. Eisenberger, et al.The Cochrane Review (20 studies), Prostate Cancer Trialists Collaborative Group (27 studies), and the Samson systematic review for AHRQ (21 trials) indicate that combined androgen blockade (maximum androgen blockade) modestly increases survival, but this is seen only at 5 years and not before that time point. The benefit seems limited to non-steroidal antiandrogens. Klotz, et al. reanalyzed the PCTCG data plus a new trial with bicalutamide utilizing a method that allows comparison of trial results that share a common arm, in this case an arm that utilizes bicalutamide. Applying this showed that bicalutimide as part of combined androgen blockade provides a modest survival advantage. The Eisenberger trial results were not included in the PCTCG analysis which was a patient-level data analysis. It was included in the Cochrane Systematic Review which utilizes a less rigorous met-analysis method. The Eisenberger trial comparing orchiectomy to orchiectomy plus flutamide found no difference in overall survival for combined androgen blockade. This was the largest intergroup trial evaluating combined androgen blockade.Neo-adjuvant and adjuvant hormone therapy with surgery or radiationCochrane Review Neo plus surgery (10) Neo plus radiotherapy (4) Adjuvant + surgery (3) Adjuvant + radiotherapy (4)Neo-adjuvant therapy prior to prostatectomy did not improve overall survival but did reduce positive surgical margins and improvement in lymph node involvement, pathologic staging, and organ confined rates. Borderline reduction in disease recurrent rates. Neo-adjuvant therapy prior to radiotherapy improved overall survival in one trial for patients with Gleason scores 2-6, but did not improve disease-specific survival in 2 trials. Adjuvant therapy following prostatectomy did not improve survival at 5 years, but one study reported improved disease-specific survival. There was improvement in disease-free survival at both 5 and 10 years. Adjuvant therapy following radiotherapy improved overall survival at 5 and 10 years. Also, an improvement in disease-free survival at 5 years. Meta-analyses & Systematic Reviews Table 9: Meta-analyses and Systematic Reviews of LHRH agonists in prostate cancer Study# TrialsPatients (N)ComparisonResultsSeidenfeld, et al. Systematic Review Meta-analysis RCTs24 10=LHRH1908 LHRH10 trials LHRH agonista vs orchiectomy or DES 13 trials antiandrogen to orchiectomy, DES, LHRH agonist, or choice of orchiectomy or LHRH agonistOverall Survival 10 LHRH trials=No statistical difference 2-yr survival HR=1.262 (95%CI 0.915-1.386) No difference between LHRH agonists compared to orchiectomy (indirect comparison) Evans, et al. Systematic Review111028 (orchiectomy) 722 (DES) 573 (cyproterone)LHRHb vs orchiectomy LHRHc vs DES LHRHd vs cyproteroneLHRH vs orchiectomy: No difference in survival LHRH vs DES: No difference in survival LHRH vs cyproterone: benefit in time to progression for goserelina LHRH= leuprolide, goserelin, buserelin b LHRH=leuprolide, buserelin, triptorelin c LHRH=goserelin, buserelin, leuprolide d LHRH=goserelin Summary: Treatment with an LHRH agonist for medical castration results in an initial rise in serum testosterone levels over 1-2 weeks, potentially worsening symptoms, followed by down regulation of receptors and a fall in the serum testosterone to castrate levels. A meta-analysis and a systematic review comparing LHRH agonist therapy to either orchiectomy or DES therapy found no improvement in survival rate, time to progression, or time to treatment failure with the use of LHRH agonists. Newer agents not included in these analyses demonstrate the ability to lower serum testosterone to castrate levels within a similar time-frame as the older agents. Effectiveness Studies Table 10: Clinical Effectiveness Trials Reference (trial design)Number of PatientsTrial Duration (wk)OutcomeResultsZinner, et al. Testosterone surge after repeat goserelin injections 3.6 mg every 28 days 10.8mg every 84 days24748Proportion with simultaneous surges of LH and serum T with repeated injections Type I: surge in LH and serum T to normal range Type 2: surge in serum T to normal range Type 3: surge in serum T greater than 18.5ng/dLSurge 3.6mg 10.8mg Type 1 0 1.8% Type 2 1.8% 0 Type 3 27% 17.7% 77.4% maintained castrate T levels (<18.5ng/dL) No reports of tumor flare during surges, but not designed to address this issueYri, et al. Failure to achieve castration levels with leuprolide Leuprolide 11.25mg depot formulation x1 Goserelin 10.8mg implant x24012-24Serum T castration levelLeuprolide: 10% failed to achieve castration levels after 3 months Goserelin: 0% failed to achieve castration levels after 6 monthsMorote, et al. Failure to maintain suppressed testosterone with long-acting 3month depot LHRH agonist Control: 90 patients Treatment: 144 patients Combined Androgen blockade=93 LHRH alone: 5123412 Serum T castration levelsLHRH (combined therapy and alone) 89.1% had serum T below 50ng/dL 10.9% did not achieve castrate levels 53.6% had serum T < 20ng/dLPathak, et al. Determining dosing interval for LHRH based on serum T Leuprolide 22.5mg administered every 3 months for 2 doses; measure serum T at 12 and 24 weeks; then repeat serum T monthly until >50ng/dL and redose; repeat serum T in 3 months and repeat sequence4272 (40-120)Duration of castrate levels (duration of action)Median dosing interval: 6 months (95%CI 5-12)Serum T=serum testosterone Quality of Life Studies Table 11: Quality of Life (QoL) with Hormone Manipulation in Prostate Cancer StudyOutcome MeasuresResultsGreen, et al. Quality of Life (QoL) during randomized pharmacologic treatment Leuprorelin Goserelin Cyproterone Observation Community (no prostate cancer)Health-care related QoL at baseline, 6, and 12 monthsSignificant effects over time for worsening HRQoL in emotional distress, physical/symptom function, social/role function and sexual function but significant group interaction for emotional distress and sexual function Increased distress over time reported in: Observation group and cyproterone group but not in LHRH groups Increased difficulties in sexual function over time pronounced in goserelin, leuprorelin, and cyproterone groups but not the observations and community groups Community group did better in cognitive changes, verbal learning tasks, and codingPotosky, et al. Evaluate sexual function and perceptions and satisfaction with either orchiectomy or LHRH agonist therapy as primary therapy Data from Prostate Cancer Outcomes Study (NCI SEER program)Health-related QoL instrument 6, 12, and 24 months after diagnosisSexual functioning Level of sexual interest: No difference Overall problem with sexual functioning: Orchiectomy: 25.6% LHRH 38.4% P=0.04 Breast swelling: greater in LHRH p<0.01 Hot flashes: No difference Physical discomfort/worry: greater in LHRH Limitations in daily activities/overall bother: No difference At 12 and 24 months more LHRH patients considered themselves not free of cancer p<0.01 Self-report of poor overall heatlh: 35.4% LHRH vs 28.1% orchiectomy p=0.01 Satisfaction with treatment decision: at least 90% in both Safety /Tolerability Rare but Serious Side Effects Flare Reaction: Initially, LHRH agonist cause an increase in LH and testosterone serum levels before desensitization and down-regulation of receptors occurs. This increase in testosterone may result in a temporary worsening of disease symptoms during the first weeks of therapy and is known as a clinical flare. This can include worsening bone pain, neuropathy, hematuria, and urethral or bladder outlet obstruction. Spinal cord compression in patients with vertebral metastases has contributed to paralysis with or without fatal complications. Patients at risk for significant events from transient disease flare include patients with obstructive voiding symptoms, significant back pain and early neuropathy, patients with extensive asymptomatic disease (PSA greater than 50-100 ng/mL) or bulky disease. The use of an antiandrogen prior to starting LHRH therapy may minimize the flare reaction. If immediate LHRH therapy is desired in a patient with high risk for a flare reaction, concomitant ketoconazole can reduce testosterone levels significantly within a few hours. Sterile Abscess,: Several cases of failure of LHRH agonists in conjunction with a local skin reaction have been reported in both children and adults. In some cases, the formation of an abscess at the injection site of one LHRH agonist has also conferred resistance to a different LHRH agonist. Potential mechanisms are formation of anti-LHRH antibodies, LHRH receptor mutation, local reaction with release of depot, and sequestration of the drug in an abscess. Required Monitoring Serum testosterone levels should be tested initially and periodically during therapy to assess maintenance of castrate levels. Most clinical trials of LHRH agonists used levels less than or equal to 50 ng/dL as castrate testosterone levels, although more recent information, including a higher sensitivity of the serum testosterone test, attempt to redefine castrate levels when testosterone reaches less than or equal to 20 ng/dL based on levels achieved with orchiectomy. Controversy exists, since no clinical benefit or survival benefit has been demonstrated with this new level. Recent data suggests a threshold value of 32 ng/dL predicts a survival advantage. Side Effect Profile General: Adverse effects of the LHRH agonists occurs corollary to the expected physiological effects of decreased testosterone levels. These agents can cause hot flashes, impotence, and reduced libido. The effects of LHRH agonists on bone turnover in men have gained more clinical importance with data on osteoporosis and bone fractures induced by androgen deprivation therapy. Table12: Treatment-emergent adverse events in >2-5% Adverse EventGoserelin ImplantHistrelin ImplantLeuprolide DepotLeuprolide SuspensionLeuprolide ImplantTriptorelin SuspensionEndocrine Hot Flashes Sexual Dysfunction Decreased Erections Gynecomastia/tenderness Testicular Atrophy Decreased libido 62 21 18 65.5 3.5 4.1 5.3 2.3 58.5 20.2 56.4 67.9 2.3 6.9 3.8 73 2.3 7 2.3Urogenital Lower urinary tract symptoms Renal Impairment 13 4.714.9 2.6 3.8  5.7Nervous System Lethargy Pain Insomnia Dizziness Headache Depression Leg cramps 8 8 5 5 2.9 26.6 8.5 6.4 6.4 3.1 4.6 5.3 6.3 1.7 2.9 6.9 1.7Skin Edema Sweating Rash Injection site reaction Pruritis Alopecia 7 6 6  5.8 8.5 13.8 2.6 3.1 5.3 2.3 6.3 1.7 4 Digestive Anorexia Nausea Constipation Diarrhea Dyspepsia Abdominal pain 5 3.516 3.4 2.3 2.9 1.7 1.1 1.7 1.1Respiratory Upper respiratory infection COPD Dyspnea Cough 7 6 6.4 2.3 1.1 1.1 1.7Musculoskeletal Bone pain Skeletal pain Joint disorder  11.7 3.4  13.2 3.4Miscellaneous Asthenia Malaise/fatigue Ecchymosis Anemia Weight gain   9.9 7.4 6 7.6 4.6 2.3 2.3 1.1 2.3 Cardiovascular Hypertension Dependent edema 4 2.3 Osteoporosis and Fractures: There is increasing evidence of skeletal risks in men receiving androgen deprivation therapy (ADT) for prostate cancer.,,, Androgen deprivation, like estrogen deprivation, causes increased bone resorption leading to osteoporosis and fractures of the hip and vertebra. Risk factors include low vitamin D blood levels, a history of alcohol excess, and smoking. A retrospective study of 174 veterans at the Madison, WI VA receiving leuprolide or goserelin evaluated the prevalence of risk factors for osteoporosis and the preventive and treatment measures undertaken. Besides ADT, the majority had at least 1 risk factor for osteoporosis. Only 13% of patients had documented bone mineral density measured. Fifty-five percent received neither calcium nor vitamin D supplementation and only 19% received both. Only 11% received antiresorptive therapy with a bisphosphonate. Approximately 14% had fractures after initiation of ADT. Prevention and treatment includes calcium and vitamin D, weight-bearing exercise, bisphosphonates (zoledronic acid, , pamidronate), or a selective estrogen receptor modulator (raloxifene Special Populations Contraindications: Known hypersensitivity to the specific LHRH and in women who are or may become pregnant. Pregnancy: Category X Tolerability and Compliance Issues Table 13: Dosage Form Tolerability Studies StudyOutcome MeasuresResultsWilliams, et al. Crossover trial between goserelin and leuprorelin to assess tolerability N=50 Goserelin monthly for 2 months Then ramdomised to: A. leuprorelin monthly for 2 months then goserelin monthly for 2 months OR B. goserelin monthly for 2 months then leuprorelin monthly for 2 months Same nurse gave each injection, no local anestheticVisual Analogue Scale (VAS) for discomfort (0=no discomfort to 10=worst discomfort) immediately after and 2 hours after each injection Questionnaire84% competed Discomfort scores Group Run-in Period 1 Period 2 A G 1.57 L 0.677 G 1.213 B G 1.53 G 1.33 L0.5 P<0.001 for scores immediately after injection for leuprorelin vs goserelin Only 1 patient dropped out because he did not want to switch agents Only 1 patient dropped out because he was reluctant to have goserelin injection without anestheticMorgan and Cooley Comparative assessment of 2 LHRH agonist administration times and RNs perception Randomized, crossover study of pre and post-registration nurses 1. Prepared and administered goserelin into a rubberized foam model then did the same with leuprorelin 2. Prepared and administered leuprorelin into a rubberized foam model then did the same with goserelinPreparation and administration times Questionnaire on ease of preparation, safety precautions, and manipulation of equipmentSummary Time to administer Goserelin Leuprorelin Mean 1.7 min 3.34 min* Median 1.5 min 3.06 min Range 0.5-3.05 1.41-6.35 *p<0.0001 Questionnaire Goserelin vs leuprorelin Easy to prepare: 91% vs 61% p<0.001 Good Safety: 85% vs 40% p<0.001 Easy to manipulate: 76% vs 64% p<0.001 Size of needle appropriate: 29% vs 67% P<0.001 Preference for goserelin system vs leuprorelin: 58% vs 42% p=0.036 Conclusion Efficacy: LHRH agonist produce castrate levels of testosterone within 3-4 weeks for most patients, and are accepted and tolerated over orchiectomy for androgen deprivation therapy (ADT). Meta-analysis has shown outcomes equivalent to either orchiectomy or DES therapy in terms of survival, time to progression, and time to treatment failure. Even though newer agents do not have comparative trial data, it is not expected that time to events will differ with these agents as they all suppress testosterone to castrate levels over time. ASCO and NCCN guidelines recommend either orchiectomy or LHRH agonist therapy for first-line hormonal treatment of advanced prostate cancer. Use in earlier stages of disease as neoadjuvant or adjuvant therapy in combination with surgery or radiation continues to evolve. Safety: All LHRH agonist cause an initial increase in serum testosterone levels that can worsen pain, obstructive urinary symptoms, spinal cord compression, and neuropathy with potential for paralysis and fatalities in select groups. Patients should be evaluated prior to starting LHRH therapy for risk factors and those at high risk should be pre-treated with an antiandrogen for 2-4 weeks before starting the LHRH agonist. Long-term androgen deprivation is now recognized as a risk factor for the development of osteoporosis in men with an increased risk for fractures. All patients should be screened at baseline and periodically during treatment for bone mineral density changes. Supplementation with oral calcium and vitamin D, along with weight-bearing exercise is recommended. The use of bisphosphonates can prevent bone loss during ADT. Only zoledronic acid has been shown to also increase bone mineral density in this population. Differences between the agents are not based on efficacy but on pharmaceutical factors such as: availability of long-acting formulations, dosage form, administration techniques, ease of preparation, and storage and handling. References Prepared by: Mark C. Geraci, Pharm.D. BCOP Points of contact: Mark C. Geraci, Pharm.D. (VA) Version 3, last major revision June 2010 Check for updated versions at:  HYPERLINK "http://www.pbm.va.gov" www.pbm.va.gov or vaww.pbm.va.gov Appendix A Table 14: Clinical trials of LHRH agonists in advanced prostate cancer StudyInclusion & Exclusion Criteria Patient PopulationRegimensResultsGoserelin Zoladex Prostate Study Group Vogelzang, et al.N=283 Stage D2 prostate cancer Excluded: h/o other malignancy Signs of spinal cord or ureteral compression, hepatic or renal impairment, previous chemo or hormone therapy for prostate cancerOrchiectomy vs Goserelin 3.6 mg subcutaneously every 28 daysMedian Serum Testosterone Week 4: 20.9 ng/dL goserelin vs 20 nd/dL orchiectomy Median Time to Treatment Failure: 52 weeks for goserelin vs 53 weeks for orchiectomy Median overall survival: 119 weeks goserelin vs 136 weeks orchiectomy Hazard Ratio for death in goserelin group: 1.12 (95%CI 0.85-1.49)Leuprolide Depot Leuprolide Study Group 1984 N= 199 Stage D2 No previous systemic therapyLeuprolide 1mg SC daily Or DES 3mg PO daily for 24 weeks Objective response (CR+PR+SD) Leuprolide 86% DES 85% Hormonal Response Leuprolide delay in fall of testosterone week 1 (p<0.01); then no difference in values Both: castration levels (<50ng/dL) after weeks 2 or 3 Prostatic Acid Phosphatase:decreased in both >25% Survival TTFirst Progression (median) Leuprolide 60 weeks DES 61 weeks NSS Overall Survival (1 year) Leuprolide 87% DES 78% NSSSharifi 1985 N= 25 Stage D2 No previous systemic therapyLeuprolide 1mg SC daily Or DES 3mg PO daily Objective response (CR + PR) Leuprolide 54.5% DES 50% Hormonal response ( testosterone levels thru week 4 in leuprolide patients , both groups similar after week 4 Prostatic acid phosphatase:normal by wk12 in responders Subjective response Similar in each group after week 4 Disease flare in 27.3% of leuprolide pts Sharifi and the Leuprolide Study Group 1990 N=53 Stage D2 No previous systemic therapyLeuprolide depot 7.5mg IM every 4 weeks Compare to historical data using 1mg SC dailyEfficacy Testosterone- castrate levels by week3-4; initial increase in levels peaking on day 4 Prostatic acid phosphatase: >25% reduction wk 12-24 Exclusions: 2 for protocol violation and 1 for irregular visits Progression in 8 (18.2%) by week 24 (similar to SC daily injections) Triptorelin Heyns, et al.N=284 Stage C or DTriptorelin 3.75 mg IM every 28 days vs Leuprolide depot 7.5mg IM every 28 daysEfficacy Testosterone castrate levels: Triptorelin Day 28 - 91% Day 57 98% Leuprolide Day 28 99% Day 57 97% Survival at 9 months: 97% triptorelin 90.5% leuprolide      VA/DoD Drug Class Review: LHRH Agonist for Prostate Cancer Page  PAGE 18 of  NUMPAGES 21 Version 3, last major revision June 2010 Check for updated versions at:  HYPERLINK "http://www.pbm.va.gov" www.pbm.va.gov or vaww.pbm.va.gov Portions of these documents or records, or information contained herein, which resulted from Pharmacy Benefits Management Drug Usage Evaluations and Utilization Review activities may be considered confidential and privileged under the provisions of 38 U.S.C. 5705 and its implementing regulations. 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