1,2,3 ABNORMAL UTERINE BLEEDING Kellie Towriss BSP  www.RxFiles.ca Jun 2015 Abnormal Uterine Bleeding (AUB)4 Goals of Treatment:10 FIGO & SOGC Classification of AUB6,16 Premenopausal: Any variation from the normal menstrual cycle, & includes changes 1. Manage underlying medical condition contributing to AUB. Causes (& some tx) of AUB in non-pregnant, reproductive aged women in regularity & frequency of menses, in duration of flow, or amount of blood loss 2. If anemia present- start iron supplementation (see below). Abnormal Uterine Bleeding during or between regular menstrual periods. 3. Manage AUB- restore predictability of menses or stop it entirely. Postmenopausal: spontaneous or unexpected uterine bleeding that occurs >1 year 4. Encourage patient to achieve & maintain healthy active lifestyle. Structural (PALM) Non-Structural (COEIN) after the last menstrual period. Important to rule out endometrial carcinoma! 5. Ensure activities of daily living (e.g. work, social) are achievable Often Surgical

4,5,6,7,8,9 Coagulopathy (AUB-C) Precipitating Causes: Treatment Considerations: Desire for fertility is often the Anatomic Causes (see examples under FIGO classification at upper right) determinant for medical vs. surgical approach. Tailor therapy to Polyps (AUB-P) Ovulatory Dysfunction (AUB-O) Systemic Causes: PCOS, obesity, uncontrolled DM, thyroid dysfunction, individual’s therapeutic goals, patient preference, patient age, Tx: LNG-IUS, DMPA, OCs, cyclic Adenomyosis (AUB-A) hyperprolactinemia, liver dx, kidney failure, leukemia, inherited bleeding contraception, underlying medical conditions or CI, presence of progestin disorders (e.g. Von willebrand’s, deficiencies in Factor XI, VII, or XIII, carrier for dysmenorrhoea, severity of bleeding & tolerance of AEs. hemophilia A or B, platelet function abnormalities), endometrial dysfunction Leiomyomas (AUB-L) Treatment Options: Surgery vs. Drug Therapy Factors to Consider6,11, 12 Endometrial (AUB-E) Drug-Related Causes: anticoagulants, antiepileptics (e.g. phenytoin, valproic acid), Medical tx: should be first line once malignancy & pelvic pathology antipsychotics (1st gen & risperidone), , herbal products (e.g. Malignancy/Hyperplasia have been ruled out due to invasiveness &  risk unless: (AUB-M) Iatrogenic (AUB-I) chasteberry,danshen, ginseng, gingko, motherwort, & soy), hormonal  Failure to respond to, or inability to utilize medical therapy (due to Tx. Hysterectomy contraceptives, levothyroxine, long-term estrogen therapy, NSAIDs, SSRIs, AE/CI); significant anemia Not Yet Specified (AUB-N) tamoxifen, TCAs; recent hx of epidural injection (<2 months). Surgical options: endometrial ablation, hysteroscopic polypectomy, 4 Initial Assessment: myomectomy, & hysterectomy (only definitive/curative treatment) * Inherited Bleeding Disorders: if typical treatments fail, consider desmopressin or History: sexual & reproductive history, impact on social functioning & QOL, thyroid Note: approx. 50% of women who receive drug therapy eventually choose factor replacement (consult hematologist)6 13,14 dysfunction, coagulation disorders, family history of cancer, coagulation surgical treatment due to refractory bleeding or desire for definitive treatment Acute Bleeding Treatment:6,10,17,18 disorders, & co-morbid conditions, Anemia Treatment Considerations (see RxFiles pg. 138 & 164)15 IV estrogen, IV tranexamic acid, or OCs/progestins at high doses or in Physical: symptoms suggestive of anemia; abnormal vaginal discharge; pelvic pain  Elemental iron (Fe++) 180-200mg/day e.g. Ferrous sulphate 900mg or pressure; weight; hirsutism (=180mg Fe++) po HS(~3 months to replenish stores) ± Folate multi-dose regimens (up to 3x/daily) Dilatation & curettage or ablation considered in urgent situations Lab: pregnancy test, CBC, TSH, prolactin, ferritin, Pap smear, STI eg. chlamydia, FSH/LH,  Best to take on empty stomach (or HS) but  GI AE; therefore can take Select Investigations: endometrial biopsy, transvaginal ultrasound, dilatation & with food but  absorption  50% Reserve hysterectomy as last resort due to  morbidity with acute curettage, hysteroscopy, saline infusion sonohysterography, bleeding disorders  Ferrous gluconate  tolerability but  Fe++ (300mg=35mg Fe++) anemia & resulting impaired healing, further bleeding, & infection Post Menopausal: endometrial sampling ± ultrasound to rule out  Recommend with Vit C >200-1000mg to  absorption If patient presents with stroke (due to anemia), consider leuprolide hyperplasia/carcinoma  SR and enteric coated forms  GI AE, but  absorption &  $ acetate to manage bleeding until therapeutic plan determined TREATMENT OVERVIEW19,20,21,22,23

After Specialist/Gynecology consult: 2nd line agents include GnRH agonists, & ulipristal

Evidence suggests LNG-IUS superior to non-surgical treatment methods Adolescents: all else being equal, patient preference toward OCs and NSAIDs *Contraindications to combined OCs: see next page for drug comparison table; can be used until menopause if Pre-Menopausal Adult: higher suspicion for disease-related causes of AUB; patient preference toward LNG-IUS. non-smokers & no additional cardiovascular risk factors (e.g. Hypertension, obesity, DM).

123 ABNORMAL UTERINE BLEEDING: Drug Comparison Charts Kellie Towriss BSP  www.RxFiles.ca Jun 2015 Form/strength Dosing $/yr Adverse Effects/ Contraindications Place in Therapy/ Evidence 24,25,26 HORMONAL OPTIONS- regulate menstrual cycle,  likelihood of unscheduled/prolonged & heavy bleeding episodes (see RxFiles pg.125-127)27  Protect endometrium from unopposed estrogen &  risk of AE: Minimal amount absorbed systemically -  hormonal AE hyperplasia/carcinoma with addition of progestin Initial $360/5yr 31 Intrauterine System Most common : irregular bleeding/spotting (esp.in first 3-6months),  women with AUB who desire reliable contraception (LNG-IUS) cramping, risk of expulsion & hormonal (breast tenderness, mood LNG-IUS28,29: Releases 20mcg daily for 5 years $70 3mos 12 mos 1yr MIRENA 52mg changes, acne) Rare: perforation, PID (low risk; more likely within ~20 days  Menstrual blood loss:  by 86% &97% , 20-80% ammenorrhic (less S OGC ‘14 after insertion); consider screen for STI risk via hx & physical exam before insertion effective than surgery for  bleeding, similar QOL) [New USA: ”Mini-Mirena” [Releases 6mcg daily for 3 years ?? CI: large intracavitary pathology, breast CA, recurrent/recent PID  Dysmenorrhea improves SKYLA 13.5mg] (Not yet available in Canada)] Note: caution with patients who are severely immunocompromised  Other: most reliable in obese & overweight women30; may be used in or at high risk for sexually transmitted infections leiomyoma, adenomyosis, & bleeding dx;  pelvic pain; efficacy for 3-5 Monophasic combined 1 tab TID until bleeding ceases (usually $235 AE: breast tenderness, mood change, fluid retention, breakthrough years but greatest  seen in first 3 months oral contraceptives (OCs), <7 days), then taper to once daily bleeding, nausea, headache (Rare: VTE, stroke, MI)  If difficult to insert in nulliparous : misoprostol 400mcg x1 inserted vaginally (30mcg Ethinyl Estradiol) taken continuously x 3 mos OR CI: history of stroke or VTE, uncontrolled HTN, migraine with 4hr prior to procedure (ensure pregnancy test negative!); insert during menses e.g. MIN-OVRAL Daily pill for 21d each month OR neurological sx, CAD, active liver dx, hx of breast CA, smoker >35yrs Combined OCs: {many opt for continuous use, without a pill-free interval}  [Alternately, NUVARING or EVRA patch & 15 cigarettes/day {Triphasics NOT suitable!}  Initial dosing varies in practice (e.g. initial 1 tab BID-QID) & duration (2-14d) cyclic or continuous, are options]   Menstrual blood loss: by 40-50% In regard to ovarian cysts: Depot 150mg IM q12weeks $110 AE: irregular BTB or spotting, breast tenderness, nausea, weight  Dysmenorrhea improves o OCs thought not to  formation gain, mood disturbance, small  in BMD reversible upon cessation DMPA: acetate DEPO-PROVERA o Progestin-only pills, LNG-IUS & CI: Pregnancy, breast CA, active liver disease, liver tumours  Menstrual blood loss: ~60-70% hysterectomy  formation slightly Progestin-only pills: Cyclic dosing AE: breast tenderness, bloating, weight gain, headaches, acne, mood changes, amenorrheic after 1st year Medroxyprogesterone irregular bleeding/spotting o Most cysts asymptomatic, small 5-10mg po from days 14- 28  Other: no published trials for AUB PROVERA,g 2.5, 5, 10mg tab 5mg po TID from day 5-26 (long-phase) $300 CI: pregnancy, breast CA, liver disease in size and resolve spontaneously Micronized Prometrium contains peanut oil; should not be used if peanut allergy Progestin-only: PROMETRIUM 100mg cap  100-200mg po HS from days 14-28 Note: long-cycle (21 days) high dose progestin shown to  heavy menstrual  Menstrual blood loss: 50% achieve menstrual regularity; cyclic luteal-phase bleeding, but AE  limits practicality is less effective than NSAIDs, tranexamic acid or danazol; luteal-phase [Norethindrone acetate NORLUTATE] [2.5-10mg po daily day 5-25 of cycle] [Norethindrone acetate (5mg) not commonly available in Canada] progestin alone not effective for heavy menstrual bleeding

NON-STEROIDAL Anti-inflammatory Agents (NSAIDs) -  total prostaglandin production to promote uterine vasoconstriction & bleeding in AUB  Non-hormonal option 17 Naproxen NAPROSYN, Initial 1000mg x 1, then 500mg BID $130 AE: GI, gastritis, dypepsia, peptic ulcers, edema, phototoxic reaction,  Menstrual blood loss by 33-55% (less effective than OCPs, tranexamic

ALEVE,g tabs,susp,supp Max: 1500mg/day (short term, 3 days) small bowel ulceration (unlikely significant in most patients since acid, LNG-IUS, & danazol); No evidence that one NSAID is more effective OTC: 220mg tab therapy only a few days per month) than another NSAID Ibuprofen ADVIL, Initial 1200mg x 1, then 600mg TID $130 Caution: Avoid in CKD stage 3 (CrCl <40ml/min), stage 4, stage 5 (unless  Dysmenorrhea improves for up to 70% of patients

MOTRIN,g tabs,susp Max: 2.4-3.2g/day dialysis), & transplant (not recommended when CrCl<30ml/min) OTC: 200 & 400mg tabs CI: hypersensitivity, severe renal dx, platelet or coagulation  May consider initial loading dose (2x regular dose) on first day 17 Mefenamic Acid PONSTAN, 500mg TID $360 disorders, pre-existing gastritis, and PUD, CrCl<30ml/min  Begin the day before menses for 3-5 days or until bleeding ceases MEFENAMIC 250mg cap Max: 7 days Note: Can be taken safely in combination with OCs for dysmenorrhea treatment ANTI-FIBRINOLYTICS - Plasminogen activator inhibitor, reversibly binds to plasminogen to  local fibrin degradation (w/o changing coagulation)  Provides symptomatic treatment only, does not address underlying cause Tranexamic Acid LYSTEDA, 1g po QID during menses (?4g po daily) OR $700 AE: N/V/D, headaches, leg cramps ?elevated VTE risk  Menstrual blood loss  by 40-59% (superior to luteal-phase progestins & CYKLOKAPRON 500mg tab, Acute: 10mg/kg IV Q6H Best choice if hormone tx CI’ed or immediate pregnancy is desired12 NSAIDs), thus very useful to reduce heavy flow short term situations (may 100mg/ml inj (5 & 10ml)  CrCl 30-60ml/min: 1300mg daily x 5d, CI: past history of VTE prescribe for “use only on heavy days”) <30ml/min: 650mg daily x 5d  Other: does not  duration of menses, regulate cycle or tx dysmenorrhea OTHER AGENTS Induces endometrial atrophy through suppression of hypothalamic-pituitary-ovarian axis (hypoestrogenic effects) Danazol CYCLOMEN 100-400mg po daily $1150 AE: more than other options: weight gain, acne, muscle cramps, GI upset,  Menstrual blood loss  by up to 80% ( doses,  extent of bleeding reduction &  AE)

50mg, 100mg, 200mg caps irritabiliy, & androgenic effects (e.g. hair growth)  Most commonly recommended by specialists (Generally used shorter-term, 6 months) CI: Liver disease GnRH agonists Long-term use limited by AE  endometrial atrophy & amenorrhea in 3-4 weeks Leuprolide 3.75mg IM monthly $4500 AE: mood changes; bone pain, BMD; hot flashes, night sweats, & vaginal  Menstrual blood loss: tx heavy menstrual bleeding LUPRON DEPOT 3.75mg, dryness. (Add low dose estrogen & progesterone in combination with GnRH  Dysmenorrhea: provides relief from dysmenorrhea associated w/ 7.5mg, 11.25mg  agonists if therapy to extend beyond 6 mos12) adenomyosis/ Goserelin ZOLADEX 3.6mg SC monthly $5000 CI: allergy, suspected pregnancy  Other: may  uterine & leiomyoma volume by 60%18 3.6mg, 10.8mg  Most commonly recommended by specialists as short-term preoperative therapy  Ulipristal FIBRISTAL  Selective modulator; inhibits cell growth & promotes apoptosis controls bleeding related to uterine fibroids & fast onset of amennorhea (7-10 days) 5mg tab 5mg po daily $1200 AE: hot flashes, headache, dyslipidemia, and breast pain  Menstrual blood loss: 91% controlled vs 19% in placebo (noninferior & more sustained Start during the first 7 days of menstrual for 3 CI: pregnant, breastfeeding & with breast, uterine, ovarian or cervical cancer effect than leuprolide acetate; effect may persist up to 6 months) 3A4 eg dabigatran etexilate, digoxin (New in Canada 2013) cycle. Safety not established in renal months DI : ulipristal is a 3A4 substrate; may  P-gp substrates  Other:  volume (31% vs placebo  3%); indicated for 3 months impairment: Monitor closely if used OCs & progestin-only pills should not be given in combination with Ulipristal New drug (2013). Further studies needed investigating long-term effectiveness & safety.

 = Exception Drug Status in SK = Non-formulary in SK  =prior approval by NIHB =not covered NIHB = covered NIHB $=retail cost = advantage AE: adverse events; AUB: Abnormal uterine bleeding; BTB: breakthrough bleeding; CA: cancer; CBC: Complete blood count; CI: contraindications; DM: Diabetes mellitus; DMPA: depot medroxyprogesterone acetate; dx: disease; Fe++: elemental iron; FIGO: International Federation of Gynecology and Obstetrics; FSH: follicle stimulating hormone; g: generic; GI: gastrointestinal; GnRH: Gonadotropin Releasing hormone; HMB: Heavy Menstrual Bleeding; IM: intramuscularly; LH: luteinizing hormone; LNG-IUS: levonorgestrel intrauterine system; MI: myocardial infarction; NSAID: non- steroidal anti-inflammatory drug; OC: Combined Oral Contraceptive; OTC: over-the-counter; PCOS: polycystic ovarian syndrome; PID: pelvic inflammatory disease; QOL: Quality of Life; SR: sustained release; SSRI: Selective Serotonin Reuptake Inhibitors; STI: sexually transmitted infections; sx: Symptoms; TCA: Tricyclic Antidepressants; TSH: Thyroid-stimulating hormone; tx: Treatment; VTE: venous thromboembolism. 124

EXTRAS – RxFiles – Abnormal Uterine Bleeding – Tx Chart

: Further investigations for Special Circumstances Bleeding Disorders-  suspicion when initial onset of menses is heavy & regular bleeding patterns or presents with suggestive sx: postpartum hemorrhage; surgery-related bleeding, & bleeding associated with dental procedures; or frequent bruising, epistaxis, and bleeding gums. Further investigations: platelet count, PTT, INR, von Willebrand factor,& ristocetin factor Peri-menopausal- consider endometrial sampling first line due to  risk of endometrial hyperplasia/carcinoma in patients >45yrs or <45 WITH hx of unopposed estrogen exposure, failed medical management, or persistent AUB

Uterine Fibroids & AUB Treatment32,33,34,35 Uterine fibroids are commonly found in women in the middle to later reproductive years & are associated with symptoms such as heavy bleeding, menstrual pain, pressure in the lower abdomen, infertiliy, & recurrent miscarriages. Uterine fibroids are thought to be estrogen and progesterone dependent because they shrink after menopause. Traditionally treatment has been the surgical route (myomectomy or hysterectomy), but drug treatments are becoming more relevant: Agents currently used for Uterine Fibroids 1. GnRH agonists:  uterine fibroid size (by 50%) &  uterine fibroid-related symptoms, but treatment restricted to 3-6 months due to hypoestrogenic AE & fibroids return to pretreatment size once agents are stopped 2. LNG-IUS MIRENA:  menstrual blood loss related to uterine fibroids &  hemoglobin in women with anemia, but is not beneficial for uterine regression 3. Ulipristal FIBRISTAL: selective progesterone receptor modulator;  uterine fibroid volume (31% vs placebo  3%); controls bleeding & faster onset of amenorrhea (noninferior & more sustained effect than leuprolide acetate); no serious side effects Agents in the Clinical Trial Pipeline for the indication of Uterine Fibroid Associated Abnormal Uterine Bleeding:  MIFEPREX: competitively binds & antagonizes progesterone receptors; inconsistent evidence on effect of uterine size reduction (0 to 50%);  endometrial hyperplasia with no atypia (unsure of clinical implications)  : selective progesterone receptor modulator with high receptor & tissue specificity; 25mg/day  volume by 36%;  bloating, pelvic pain, & uterine artery blood flow; minimal hypoestrogenic effects  PROELLEX: selective progesterone modulator; doses of 12.5, 25, & 50mg  fibroid size by 10.6, 32.6, & 40.3% respectively (leuprolide acetate 32.6% & placebo 10.6% )  Aromatase inhibitors (letrozole, anastrozole, fadrozole): antiestrogen;  size of fibroid & symptoms (menstrual volume, duration of menstruation, & dysmenorrhea); no serious side effects reported

1 Singh S, Best C, Dunn S, Leyland N, Wolfman WL, et al.; Clinical Practice – Gynaecology Committee; Society of Obstetricians and Gynaecologists of Canada. Abnormal uterine bleeding in pre-menopausal women. J Obstet Gynaecol Can. 2013 May;35(5):473-9. 2 Davidson BR, Dipiero CM, Govoni KD, Littleton SS, Neal JL. Abnormal uterine bleeding during the reproductive years. J Midwifery Womens Health. 2012 May-Jun;57(3):248-54. 3 Sweet MG, Schmidt-Dalton TA, Weiss PM, Madsen KP. Evaluation and management of abnormal uterine bleeding in premenopausal women. Am Fam Physician. 2012 Jan 1;85(1):35-43. 4 Bordman R, Telner D, Jackson B, Little D, Gamache N. An Approach to the diagnosis and management of benign uterine conditions in primary care. Second. 2010. Centre for Effective Practice and Ontario College of Family Physicians. Accessed October 4, 2013 from: http://machealth.ca/programs/buc/m/resources/26.aspx. 5 Ely JW, Kennedy CM, Clark EC, Bowdler NC. Abnormal uterine bleeding: a management algorithm. J Am Board Fam Med. 2006 Nov-Dec;19(6):590-602. 6 American College of Obstetricians and Gynecologists. ACOG committee opinion no. 557: Management of acute abnormal uterine bleeding in nonpregnant reproductive-aged women. Obstet Gynecol. 2013 Apr;121(4):891-6. 7 Morrell MJ, Hayes FJ, Sluss PM, et al. Hyperandrogenism, ovulatory dysfunction, and polycystic ovary syndrome with versus lamotrigine. Ann Neurol. 2008;64(2):200–211. 8 Madhusoodanan S, Parida S, Jimenez C. Hyperprolactinemia associated with psychotropics—a review. Hum Psychopharmacol. 2010;25(4):281–297. 9 O'Malley P. Selective serotonin reuptake inhibitors and abnormal bleeding. Implications for the clinical nurse specialist. Clin Nurse Spec. 2004 Mar-Apr;18(2):65-7. 10 Committee on Practice Bulletins—Gynecology. Practice bulletin no. 136: management of abnormal uterine bleeding associated with ovulatory dysfunction. Obstet Gynecol. 2013 Jul;122(1):176-85. 11 Matteson KA, Abed H, Wheeler TL 2nd, Sung VW, Rahn DD, Schaffer JI, Balk EM;Society of Gynecologic Surgeons Systematic Review Group. A systematic review comparing hysterectomy with less-invasive treatments for abnormal uterine bleeding. J Minim Invasive Gynecol. 2012 Jan-Feb;19(1):13-28. 12 Marret H, Fauconnier A, Chabbert-Buffet N, Cravello L, Golfier F, Gondry J, Agostini A,et al.; CNGOF Collège National des Gynécologues et Obstétriciens Français. Clinical practice guidelines on menorrhagia: management of abnormal uterine bleeding before menopause. Eur J Obstet Gynecol Reprod Biol. 2010 Oct;152(2):133-7. 13 Learman LA, Summitt RJ, Varner RE, et al. Hysterectomy versus expanded medical treatment for abnormal uterine bleeding: clinical outcomes in the medicine or surgery trial. Obstet Gynecol. 2004;103(5):824-833. 14 Showstack J, Lin F, Learman LA, et al. Randomized trial of medical treatment versus hysterectomy for abnormal uterine bleeding: resource use in theMedicine or Surgery (Ms) trial. Am J Obstet Gynecol. 2006;194(2):332-338. 15 Jensen B, Regier L, Downey S, Karlson P, Taylor J. RxFiles Over the Counter Products Summary Chart. RxFiles, Drug Comparison Charts, 9th edition. 2012. Accessed online at: http://www.rxfiles.ca/rxfiles/uploads/documents/members/CHT-OTCs.pdf 16 Munro MG, Critchley HO, Broder MS, Fraser IS; FIGO Working Group on Menstrual Disorders. FIGO classification system (PALM-COEIN) for causes of abnormal uterine bleeding in nongravid women of reproductive age. Int J Gynaecol Obstet. 2011 Apr;113(1):3-13. 17 Telner DE, Jakubovicz D. Approach to diagnosis and management of abnormal uterine bleeding. Can Fam Physician. 2007 Jan;53(1):58-64. 18 Shawki O, Wahba A, Magon N. Abnormal uterine bleeding in midlife: The role of levonorgestrel intrauterine system. J Midlife Health. 2013 Jan;4(1):36-9. 19 Duckitt K. Medical management of perimenopausal menorrhagia: an evidence-based approach. Menopause Int. 2007 Mar;13(1):14-8. 20 Beasley A. Contraception for specific populations. Semin Reprod Med. 2010 Mar;28(2):147-55. 21 World Health Organization, Department of Reproductive Health. Medical elgibility criteria for contraceptive use, fourth edition. 2010. 22 Hardman SM, Gebbie AE. Hormonal contraceptive regimens in the perimenopause. Maturitas. 2009 Jul 20;63(3):204-12. 23 Lidegaard Ø. Hormonal contraception and venous thromboembolic risk in midlife women. Maturitas. 2013 Jan;74(1):1-2. 24 Kaunitz, A., Inki, P. The Levonorgestrel-Releasing Intrauterine System in Heavy Menstrual Bleeding. Drugs. 2012;72 (2):193-215. 25 ACOG Practice Bulletin No. 110: noncontraceptive uses of hormonal contraceptives. Obstet Gynecol. 2010 Jan;115(1):206-18. 26 Inki P, Hurskainen R, Palo P, Ekholm E, Grenman S, Kivelä A, Kujansuu E, Teperi J, Yliskoski M, Paavonen J. Comparison of ovarian cyst formation in women using the levonorgestrel-releasing intrauterine system vs. hysterectomy. Ultrasound Obstet Gynecol. 2002 Oct;20(4):381-5.

27 Regier L, Downey S. RxFiles Hormonal Contraception Summary Chart. RxFiles, Drug Comparison Charts, 9th edition. 2012. Accessed online at: http://www.rxfiles.ca/rxfiles/uploads/documents/members/CHT-OCs-Color.pdf 28 Espey E. Levonorgestrel intrauterine system--first-line therapy for heavy menstrual bleeding. N Engl J Med. 2013 Jan 10;368(2):184-5. 29 Palmara V, Sturlese E, Villari D, Giacobbe V, Retto A, Santoro G. Levonorgestrel-releasing intrauterine device in the treatment of abnormal uterinebleeding: a 6- and 12-month morphological and clinical follow-up. Aust N Z J Obstet Gynaecol. 2013 Aug;53(4):381-5. 30 Robinson JA, Burke AE. Obesity and hormonal contraceptive efficacy. Womens Health (Lond Engl). 2013 Sep;9(5):453-66. 31 Madden T, Proehl S, Allsworth JE, Secura GM, Peipert JF. Naproxen or estradiol for bleeding and spotting with the levonorgestrel intrauterine system: a randomized controlled trial. Am J Obstet Gynecol. 2012 Feb;206(2):129.e1-8 32 Tristan M, Orozco LJ, Steed A, Ramírez-Morera A, Stone P. Mifepristone for uterine fibroids. Cochrane Database Syst Rev. 2012 33 Therapeutic Research Center. New Drug: Fibristal (Ulipristal). Pharmacist’s Letter.2013. 34 Sangkomkamhang US, Lumbiganon P, Laopaiboon M, Mol BW. orprogestogen-releasing intrauterine systems for uterine fibroids. Cochrane Database Syst Rev. 2013. 35 Islam MS, Protic O, Giannubilo SR, Toti P, Tranquilli AL, Petraglia F, Castellucci M, Ciarmela P. Uterine leiomyoma: available medical treatments and new possible therapeutic options. J Clin Endocrinol Metab. 2013 Mar;98(3):921-34.

Additional References: ACOG: American College of Obstetricians and Gynecologists.Committee Opinion No. 580. Von Willebrand Disease in women. Obstet Gynecol 2013 Dec; 122:1368. Ammerman SR, Nelson AL. A new -only medical therapy for outpatient management of acute, abnormal uterine bleeding: a pilot study. Am J Obstet Gynecol. 2013 Jun;208(6):499.e1-5. Bs D, Nanda SK. The role of sevista in the management of dysfunctional uterine bleeding. J Clin Diagn Res. 2013 Jan;7(1):132-4. Committee on Practice Bulletins—Gynecology. Practice bulletin no. 128: diagnosis of abnormal uterine bleeding in reproductive-aged women. Obstet Gynecol. 2012 Jul;120(1):197-206. Cooper NA, Barton PM, Breijer M, et al. Cost-effectiveness of diagnostic strategies for the management of abnormal uterine bleeding (heavy menstrual bleeding and post-menopausal bleeding): a decision analysis. Health Technol Assess. 2014 Apr;18(24):1-202. Cooper NAM, Clark TJ, Middleton L, Diwakar L, Smith P, Denny E, et al. Outpatient versus inpatient uterine polyp treatment for abnormal uterine bleeding: randomised controlled non-inferiority study. BMJ 2015;350:h1398. Deligeoroglou E, Karountzos V, Creatsas G. Abnormal uterine bleeding and dysfunctional uterine bleeding in pediatric and adolescent gynecology. Gynecol Endocrinol. 2013 Jan;29(1):74-8. Farquhar C. Oral contraceptive pill for heavy menstrual bleeding. Cochrane Database Syst Rev. 2009. Ker K, Prieto-Merino D, Roberts I. Systematic review, meta-analysis and meta-regression of the effect of tranexamic acid on surgical blood loss. Br J Surg 2013;100:1271–9. Lethaby a, Cooke I, Rees MC. Progesterone or progestogen-releasing intrauterine systems for heavy menstrual bleeding. Cochrane Database Syst Rev. 2010. Lethaby A, Duckitt K, Farquhar C. Non-steroidal anti-inflammatory drugs forheavy menstrual bleeding. Cochrane Database Syst Rev. 2013. Lethaby A, Farquhar C, Cooke I. Antifibrinolytics for heavy menstrual bleeding. Cochrane Database Syst Rev. 2010. Lethaby A, Hussain M, Rishworth JR, et al. Progesterone or progestogen-releasing intrauterine systems for heavy menstrual bleeding. Cochrane Database Syst Rev. 2015 Apr 30;4:CD002126. The levonorgestrel-releasing intrauterine device (LNG IUS) is more effective than oral medication as a treatment for heavy menstrual bleeding (HMB). It is associated with a greater reduction in HMB, improved quality of life and appears to be more acceptable long term but is associated with more minor adverse effects than oral therapy.When compared to endometrial ablation, it is not clear whether the LNG IUS offers any benefits with regard to reduced HMB and satisfaction rates and quality of life measures were similar. Some minor adverse effects were more common with the LNG IUS but it appeared to be more cost effective than endometrial ablation techniques.The LNG IUS was less effective than hysterectomy in reducing HMB. Both treatments improved quality of life but the LNG IUS appeared more cost effective than hysterectomy for up to 10 years after treatment. Hoellen F, Griesinger G, Bohlmann MK. Therapeutic drugs in the treatment of symptomatic uterine fibroids. Expert Opin Pharmacother. 2013 Oct;14(15):2079-85. Manno D, Ker K, Roberts I. How effective is tranexamic acid for acute gastrointestinal bleeding? BMJ. 2014 Feb 17;348:g1421. Matteson KA, Rahn DD, Wheeler TL 2nd, Casiano E, Siddiqui NY, Harvie HS, Mamik MM, Balk EM, Sung VW; Society of Gynecologic Surgeons Systematic Review Group. Nonsurgical management of heavy menstrual bleeding: a systematic review. Obstet Gynecol. 2013 Mar;121(3):632-43. McNamara M, Batur P, DeSapri KT. In the Clinic: Perimenopause. Ann Intern Med. 2015 Feb 3;162(3):ITC1. Middleton LJ, Champaneria R, Daniels JP, Bhattacharya S, Cooper KG, Hilken NH, et al. Hysterectomy, endometrial destruction, and levonorgestrel releasing intrauterine system (Mirena) for heavy menstrual bleeding: systematic review and meta-analysis of data from individual patients. BMJ. 2010 Aug 16;341:c3929. Peragallo Urrutia R, Coeytaux RR, McBroom AJ, Gierisch JM, Havrilesky LJ, Moorman PG, Lowery WJ, Dinan M, Hasselblad V, Sanders GD, Myers ER. Risk of Acute Thromboembolic Events With Oral Contraceptive Use: A Systematic Review and Meta-analysis. Obstet Gynecol. 2013 Aug;122(2, PART 1):380-389. Pinkerton JV. Pharmacological therapy for abnormal uterine bleeding. Menopause. 2011 Apr;18(4):453-61. Roberts TE, Tsourapas A, Middleton LJ, Champaneria R, Daniels JP, Cooper KG, et al. Hysterectomy, endometrial ablation, and levonorgestrel releasing intrauterine system (Mirena) for treatment of heavy menstrual bleeding: cost effectiveness analysis. BMJ. 2011 Apr 26;342:d2202. Rott H. Thrombotic risks of oral contraceptives. Curr Opin Obstet Gynecol.2012 Aug;24(4):235-40. 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Pictured at left: 1) RxFiles Drug Comparison Charts 10th Ed. 2) Geri-RxFiles – Assessing in Older Adults

RxFiles – Abnormal Uterine Bleeding – Tx Chart

Developed by Kellie Towriss, BSP (Pharmacy Resident, Saskatoon Health Region (2013; last revised, June 2015)

Acknowledgements to those who assisted with development and review of this chart & topic: Obs/Gyne: Dr. L. Regush, Dr. M. Shubert, Dr. A. Epp Family Physicians: Dr. J. Hey, Dr. R. Reineger, Dr. S. Fenton, Dr. S. Wegner (Additional 2015: Dr. N. McKee, Dr. J. Blazer, Dr. T. Laubscher) RxFiles Pharmacists: B. Jensen, L. Regier, L. Kosar, B. Schuster

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