9/13/2018 Pediatric Pharmacy Advocacy Group Missing Menses: Preventing the Menstrual Cycle and Emergent Therapy for Breakthrough Bleeding Tara Wright, PharmD, BCPPS Seattle Children’s Hospital Objectives • Identify gynecologic concerns in adolescent females undergoing cancer therapy • Summarize supportive care recommendations for a patient receiving leuprolide acetate • Discuss pros and cons of preventative therapies for menstrual suppression • Recognize therapies that can be utilized for emergent management of breakthrough bleeding Audience Experience • My institution has a guideline for managing menstrual suppression • I manage menstrual suppression regimens regularly 1 9/13/2018 Terminology Term Definition Amenorrhea No bleeding for ≥ 6 months in a nonmenopausal woman Menorrhagia Heavy regular menstrual cycles with heavy bleeding of > 80 mL or a duration of > 7 days Menometrorrhagia Excessive menstrual bleeding at regular intervals Metrorrhagia Bleeding between periods or irregular bleeding Oligomenorrhea Intermenstrual bleeding occurring at intervals > 35 days apart Polymenorrhea Menstrual bleeding occurring at intervals < 21 days apart Bates JS, et al. Pharmacotherapy. 2011;31:1092-1110. Abnormal Uterine Bleeding (AUB) • Change in menstrual cycle, amount of blood loss, duration of flow, or menses frequency • AUB can significantly alter quality of life – 10-30% of women experience menorrhagia • 20% of ambulatory care visit due to menstruation issues • Among adolescents, 34-51% report experiencing oligomenorrhea and polymenorrhea Bates JS, et al. Pharmacotherapy. 2011;31:1092-1110. Nicholson WK. Am J Obstet Gynecol. 2001; 184:523-30. Rigon F. Italian Journal of Pediatrics. 2012;38:38. Cancer and AUB • Diagnosis of cancer in females aged 15-19 years – 20 cases per 100,000 individuals per year • Cancer therapy and uterine toxicity – Radiation • Effects vary by site and dose – Chemotherapy • Gonadotoxicity influenced by age and type of treatment • Hormonal disturbance and dysfunctional uterine bleeding – Surgery • Site of surgery and organs removed may affect fertility Bates JS, et al. Pharmacotherapy. 2011;31:1092-1110. Centers for disease control and prevention. MMWR recomm Rep. 2010;59(RR-1):1-86. Obstet Gynecol. 2014;124(2):403-408. 2 9/13/2018 Gynecologic Concerns • Pubertal development • Heavy menstrual bleeding and anemia • Contraception • Ovarian insufficiency • Breast and cervical cancer screening • Fertility • Pregnancy outcomes Obstet Gynecol. 2014;124:397-402. Complications in Oncology Patients Increased Worsening Increased transfusion thrombocytopenia morbidity requirement Bates JS, et al. Pharmacotherapy. 2011;31:1092-1110. Meirow D, et al. Cancer. 2006;107(7):1634-1641. Obstet Gynecol. 2014;124:397-402. Shipman C. JHOP. 2015;5(3):70-73. Menstrual Cycle https://medium.com/@bicspuc/menstrual-cycle-an-important-process-of-human-reproduction-e22a4abce2e2 Bates JS, et al. Pharmacotherapy. 2011;31:1092-1110. 3 9/13/2018 Hormone regulation of the Menstrual Cycle GnRH = gonadotropin release hormone; FSH = follicle stimulating hormone; LH = luteinizing hormone Hawkins S, et al. Ann N Y Acad Sci. 2008;1135:10-18. Bates JS, et al. Pharmacotherapy. 2011;31:1092-1110. Preventative Therapy • Goal: prevention of menorrhagia – severe vaginal bleeding cause of significant morbidity • Therapy Options 1) Estrogen/progestin oral contraceptive pills (OCP) 2) Transdermal system 3) Progestin only (various dosage forms) • Intramuscular/oral medroxyprogesterone acetate • Norethindone acetate 4) Gonadotropin-releasing hormone (GnRH) agonist • Leuprolide acetate Bates JS, et al. Pharmacotherapy. 2011;31:1092-1110. Obstet Gynecol. 2014;124:397-402. Shipman C. JHOP. 2015;5(3):70-73. Prevention of Heavy Menstrual Bleeding (HMB) Quinn S, et al. Curr Opin Pediatr. 2016;28:421-427. 4 9/13/2018 Preventative Therapy Considerations What to think about when choosing best option: Ability to take oral medications Patients’ risk of thromboembolism Contraindication to intramuscular (IM) injections Need for contraception Ovarian preservation Bates JS, et al. Pharmacotherapy. 2011;31:1092-1110. Obstet Gynecol. 2014;124:397-402. Oktay K, et al. J Clin Oncol. 2018;36:1994-2001. Shipman C. JHOP. 2015;5(3):70-73. GONADOTROPIN RELEASING HORMONE AGONIST GnRH Agonist • Leuprolide acetate is a synthetic GnRH agonist • Mechanism – Prolonged exposure results in desensitization of GnRH receptors – Decrease in synthesis and secretion of LH and FSH • Generally considered agent of choice due to consistent ability to lead to amenorrhea – Lower failure rates observed when started at least 2 weeks prior to onset of thrombocytopenia • 73-96% reduction in menstrual blood flow – Flare-bleeding may occur during the first 2-3 weeks after injection Bates JS, et al. Pharmacotherapy. 2011;31:1092-1110. Obstet Gynecol. 2014;124:397-402. Quaas A, et al. Eur J Obstet Gynecol Reprod Biol. 2007;134:3-8 Shipman C. JHOP. 2015;5(3):70-73. 5 9/13/2018 Leuprolide Options Drug Dosing Side effects Lupron Depot® 3.75 mg IM monthly Hot flashes, night sweats, mood swings, bone mineral density loss with use > 6 months, potential Lupron Depot® – 3 month 11.25 mg IM q 3 months benefit on fertility preservation Considerations • Clinical: ↓ injecons during thrombocytopenic state with 3 month depot • Cost: no significant difference between 1 month and 3 month depot • Safety: multiple products on formulary confusion when prescribing/dispensing Bates JS, et al. Pharmacotherapy. 2011;31:1092-1110. Leuprolide acetate. Lexi-comp™. Accessed August 1, 2018. Obstet Gynecol. 2014;124:397-402. Leuprolide Literature Study Methods Results Notes Sica S, et al. AML (n = 16) -No difference in frequency, duration of Both groups experienced (1996) bleeding or transfusion support. vaginal bleeding cessation; OCP vs. OCP (16 days) + leuprolide induced longer Prospective leuprolide 3.75 mg SQ q28 days - OCP only group: ↑ vaginal bleeding aer last amenorrhea stopping OCP in OCP group (p = 0.009) -OCP only group: grade III-IV liver toxicity Lhomme C, et al. Hematologic malignancy, age 18- -85% of women had no clinically relevant Increased risk of (2001) 48 years (n = 21) vaginal bleeding osteoporosis observed if leuprolide use >6 months Prospective Nomegestrol acetate 5 mg/day -67% of the severe bleeding events on days 1-35 + leuprolide 3.75 occurred after the first leuprolide dose Supports need for mg SQ q28 days (flare effect) progestin therapy past second leuprolide injection Meirow D, et al. No treatment (n = 20) Rates of bleeding: No difference in inducing (2006) vs. -No treatment - 65% amenorrhea between DMPA 150 mg IM q3 mo (n = 42) -DMPA - 55% treatment groups vs. -Leuprolide - 23% Retrospective leuprolide 3.75 mg IM q28 days Higher rates of bleeding (n = 39) Moderate to severe bleeding: with DMPA vs. leuprolide -No treatment – 40% -DMPA – 21.4% -Leuprolide – 0% Lhomme C, et al. Leuk Lymph. 2001;42:1033-41. Meirow D, et al. Cancer. 2006;107:1634-41. Sica S, et al. Am J Hematol. 1996;51:248-9. GnRH Agonists Considerations • Hypoestrogenic state can lead to vasomotor symptoms and bone density loss – Hormonal add-back therapy can preserve bone mass and reduce vasomotor symptoms • Norethindrone acetate 5 mg PO daily or • OCP (e.g. EE/norethindrone 0.03 mg/1.5 mg PO daily) • Potential benefit on fertility preservation – Conflicting data; should not be used in place of proven fertility preservation methods Bates JS, et al. Pharmacotherapy. 2011;31:1092-1110. Oktay K, et al. J Clin Oncol.2018;36:1994-2001. 6 9/13/2018 Bone Density and GnRH Agonists • Adolescence is a critical time period for accrual of bone mineral density (BMD) • GnRH agonists increase bone turnover and possible prevent attainment of peak BMD in adolescents • Occurs with prolonged exposure (>6 months) – Potentially irreversible – Therapy restricted to 6 months vs. period of duration of myelosuppressive chemo DiVasta A, et al. J Pediatr Adolesc Gynecol. 2007;20(5):293-297. Surrey E, et al. Obstet Gynecol. 2002;99(5):709-719. Taga M, et al. Acta Obset Gynecol Scand. 1996;75:162-165. Managing Bone Health • Education and awareness among all providers • Calcium and vitamin D monitoring & supplementation • Consider utility of DEXA scan • Add back therapy with norethindrone acetate Vitamin D Monitoring • 25-hydroxy vitamin D levels (every 3-6 months) – Normal: > 30 ng/mL – Insufficient: 16-30 ng/mL – Deficient: 5-15 ng/mL – Severely deficient: < 5 ng/mL • Supplementation – Calcium (1200-1500mg daily) – Vitamin D (400-800IU daily) • Consider DEXA scans Kaya A, et al. West Indian Med J. 2015;64(2):104-107. Kidney International. 2009. 76 (Suppl 113), S9–S2. Mitwally M, et al. Menopause. 2002;9(4):236-241. 7 9/13/2018 Lupron Add-back Study Group • Hornstein M, et al (1998) – Purpose: evaluate the efficacy and safety of leuprolide acetate alone and in combination with hormonal add- back therapy – Methods: all patients received IM leuprolide with add- back therapy • Group A: placebo for progestin and estrogen • Group B: norethindrone acetate 5 mg daily and placebo for estrogen • Group C: norethindrone acetate 5 mg daily and conjugated estrogens 0.625 mg daily • Group D: norethindrone acetate 5 mg daily and conjugated estrogens 1.25 mg daily Hornstein, et al. Obstet Gynecol. 1998;91:16-24. Bone Mineral Density (BMD) Results Group A Group B Group C Group D (placebo) (progestin + (progestin + (progestin + placebo) estrogen) higher dose estrogen) BMD (g/cm2) Baseline 1.030 ± 0.111 1.030 ± 0.128 1.060 ± 0.113 1.044 ± 0.121 Week 24 1.016 ± 0.113 1.046 ± 0.130