clinical practice guideline endometriosis

8/13/2019 clinical practice guideline endometriosis

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Clinical Practice Guidelines for Pharmaceutical Treatment of

EndometriosisMinistry of HealthDepartment of Health CareOrdinance no. 144 of 31 March 2010. (Amended 27 August 2010)Consultants: Cludia Vieira Mengarda, Joo Sabino Cunha Filho, Brbara Corra Krug, andKarine Medeiros AmaralEditors: Paulo Dornelles Picon, Maria Inez Pordeus Gadelha, and Alberto BeltrameThe authors have declared no conflicts of interest.

1 LITERATURE SEARCH STRATEGYA literature search was conducted using MEDLINE/PubMed (http://www.ncbi.nlm.nih.gov/pubmed).The search was limited to meta-analyses and randomized clinical trials (RCTs) published inPortuguese, Spanish, and English between 1999 and 2010. The following search terms were used:(1999 [Publication Date]: 3000 [Publication Date]) AND (Endometriosis/ drug therapy[MeSH]).A total of 4 meta-analyses and 82 RCTs were retrieved. Since the principal symptoms ofendometriosis are pelvic pain and infertility, and patients with infertility alone were consideredSpecial Cases in this CPG, 4 meta-analyses and 44 RCTs assessing pain relief after treatmentwere used in this CPG. A total of 27 studies in which pain symptoms were not assessed and 12RCTs published in languages other than Portuguese, Spanish, or English were excluded from theanalysis.

2 INTRODUCTIONEndometriosis is a gynecological disease defined as the development and growth of stroma andendometrial glands outside the uterine cavity, resulting in a chronic inflammatory reaction.

1 The

disease is diagnosed almost exclusively in women of reproductive age; postmenopausal womenaccount for only 2-4% of all cases undergoing laparoscopy for suspected endometriosis.

2

Endometriosis prevalence is difficult to determine because there is no correlation betweensymptoms and severity of the disease and also because an invasive procedure (laparoscopy) isrequired to confirm diagnosis.

3,4 The prevalence rate is estimated at about 10%. Among infertile

women, these values can reach high rates (30-60%).5

The most commonly affected sites are theovaries, anterior and posterior cul-de-sac, posterior leaflet of the broad ligament, uterosacralligaments, uterus, fallopian tubes, sigmoid colon, appendix, and round ligaments.

6

Attempts to explain the pathogenesis of endometriosis involve several theories that point to multiplecauses, involving genetic factors, immunologic abnormalities, and endometrial dysfunction.

4,6

According to the implantation theory, retrograde menstruation allows endometrial tissue to haveaccess to pelvic structures through the fallopian tubes to seed the peritoneal cavity, thusestablishing blood flow to the endometrial tissue and inducing an inflammatory response.

7 The

coelomic metaplasia theory proposes that undifferentiated cells of the pelvic peritoneum have theability to differentiate into endometrial tissue. The direct transplantation theory is the probableexplanation for endometriosis that develops in episiotomy, cesarian section, and other scars aftersurgery. Dissemination of endometrial cells or tissue through blood and lymph vessels is theprobable explanation for sites of endometriosis outside the pelvic cavity.

The principal clinical manifestations of endometriosis are infertility and pelvic pain dysmenorrhea,dyspareunia, and cyclic pelvic pain.

8,9Symptoms related to atypical sites of endometrial tissue may

also be present, such as pleuritic pain, hemoptysis, headache or seizures, painful lesions in surgicalscars, edema, and bleeding site.

2Physical examination is of limited diagnostic value in this disease,

due to the absence of pathognomonic findings. Physical findings suggestive of endometriosisinclude pain on palpation of the cul-de-sac and uterosacral ligaments, palpation of nodules oradnexal masses, and a fixed retroverted uterus.

1,2

The most commonly used staging system is the revised American Society For ReproductiveMedicine (ASRM) classification of endometriosis,

10,11which takes into consideration extent, depth,


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and location of endometriotic implants and severity of adhesions. The ASRM endometriosisclassification system contains 4 stages: stage I (minimal endometriosis) isolated implants without significant adhesions; stage II (mild endometriosis) superficial implants less than 5 cm in diameter, without significantadhesions; stage III (moderate endometriosis) multiple implants, with evident periovarian and peritubaladhesions; stage IV (severe endometriosis) multiple superficial and deep implants, including dense andthick endometriomas and adhesions.Stage IV endometriosis accounts for the most extensive disease. However, disease stage is notcorrelated with prognosis or severity of pain.

3,4 Pain severity is influenced by the depth of

endometriotic implants and their location in highly innervated areas.12,13

3 INTERNATIONAL STATISTICAL CLASSIFICATION OF DISEASES AND RELATED HEALTHPROBLEMS (ICD-10) N80.0 Endometriosis of uterus N80.1 Endometriosis of ovary N80.2 Endometriosis of fallopian tube N80.3 Endometriosis of pelvic peritoneum N80.4 Endometriosis of rectovaginal septum and vagina

N80.5 Endometriosis of intestine N80.8 Other endometriosis

4 DIAGNOSISAccording to consensus guidelines of the European Society of Human Reproduction andEmbryology (ESHRE) and the American Society for Reproductive Medicine (ASRM), the goldstandard for diagnosis of endometriosis is visual inspection of the pelvis and implants atlaparoscopy. Biopsy for histopathological confirmation is not considered to be necessary.

1,11

Although biopsy has traditionally been recommended for histological correlation in all areassuggestive of endometriosis, a number of authors have reported extremely high correlationsbetween laparoscopic and histologic findings (97-99%),

14no longer requiring histologic confirmation

and thus preventing further or unnecessary investigation of these patients. An apparent discrepancybetween studies examining the need for biopsy results from different designs and number of cases

evaluated. The diagnosis of endometriosis may be ruled out in patients with normal-appearingperitoneum.

15

5 INCLUSION CRITERIAPatients may be included in this CPG for treatment with danazol or GnRH analogues if they meetthe following eligibility criteria: pelvic pain as a clinical symptom to be treated; unresponsiveness to previous 6-month treatment with oral contraceptives or progestagens orrecurrence of endometriosis-related pain symptoms; evidence of endometriosis at laparoscopy/laparotomy, as established and reported in writing by aphysician according to the revised ASRM classification, or anatomicopathologic confirmation ofperitoneal biopsy.

6 EXCLUSION CRITERIAPatients should be excluded from this CPG if they meet any of the following criteria: pregnancy (possible androgenic effects in female fetuses); breastfeeding; genital bleeding of unknown origin (only for danazol treatment); severe hepatic dysfunction (only for danazol treatment); hypersensitivity to the drug.

7 SPECIAL CASES


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Danazol administration in patients with porphyria (the drug may exacerbate the disease) or inpatients with a history of thromboembolic event Use of oral contraceptives by smokers aged > 35 years (higher risk of thromboembolism) Indication of retreatment or treatment for a longer period of time

8 TREATMENTThe choice of treatment will depend on the severity of symptoms, the extent and location ofdisease, whether there is a desire for pregnancy, and the age of the patient. Patients may undergodrug therapy or surgical treatment, or even a combination of both.

5Effectiveness of treatment has

been associated with pain relief and improved fertility rates.5All hormonal treatments are effective

in relieving pain attributed to endometriosis when compared with placebo and are equally effectivewhen compared to each other.

9

Drug therapy focuses mainly on hormonal manipulation in order to induce pseudopregnancy,pseudomenopause, or chronic anovulation, thus setting an environment unsuitable for growth andmaintenance of endometriotic implants.

4

Hormonal suppression of ovulation in women with infertility is deemed unnecessary.4 Clinical

treatment is not indicated for patients with endometriosis-related infertility because the commonlyused drugs are not effective in this setting.

16,17Surgical intervention with electrocautery destruction

of implants has proven effective in the treatment of infertile women with stage I and IIendometriosis. A multicenter study evaluating 341 infertile women with minimal to moderate

endometriosis showed significantly higher pregnancy rates in the group assigned to undergolaparoscopy with resection or ablation of endometriosis.

18 Therefore, after electrocautery of

endometriotic implants, this group may be treated for infertility.Several surgical and clinical approaches have been tested for the treatment of endometriosis.Treatment decisions should take into account clinical manifestations whether pain or infertility ,patient age and history of reproduction, and the extent of disease. Cases in which laparoscopy isindicated should undergo surgical resection or ablation of the largest number of endometrioticimplants.

19

8.1 CLINICAL TREATMENT

Oral contraceptives (OC)The use of OCs should be considered for empirical treatment in women with symptoms and

physical examination findings suggestive of endometriosis, provided that other diseases associatedwith pelvic pain have been ruled out.

1This treatment produces a delay in disease progression as

well as protection in cases in which there is no desire for pregnancy.20

A study comparingadministration of OC (ethinyl estradiol 0.035 mg + norethisterone 1 mg) with placebo showed asignificant decrease in dysmenorrhea and nonmenstrual pain scores assessed by the verbal ratingscale and the visual analog scale in both groups; however, both dysmenorrhea and nonmenstrualpain were significantly milder in the OC group (-2) than in the placebo group (-0.6).

21The volume of

endometrioma was significantly decreased in the OC group, but not in the placebo group. Noserious adverse events were observed in the OC group, although this group showed a higherincidence of nausea and irregular bleeding. An important potential bias in that study concerns thefact that only 10 women in the OC group and 7 in the placebo group had a laparoscopic diagnosisof endometriosis. Ultrasound scanning has limited value as a diagnostic tool for peritonealendometriosis,

1 and there may have been more patients with deep peritoneal endometriosis and

persistence of pain in the placebo group.Cyclic OCs have been compared with GnRH agonists. GnRH agonists were more effective inrelieving dysmenorrhea, but OCs and GnRH agonists were equally effective in reducingdyspareunia and nonspecific pelvic pain.

22A randomized clinical trial comparing OCs with goserelin

showed that OCs were more effective in the management of dysmenorrhea and that goserelin wassuperior to OCs in reducing dyspareunia.

23 An open multicenter clinical trial showed that both

treatments are effective in improving dysmenorrhea and nonmenstrual pelvic pain, with nodifferences in response between treatments.

24

Danazol


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dyspareunia, and nonmenstrual pelvic pain scores. According to an intention-to-treat analysis, 62%of patients in the OC group were satisfied or very satisfied with the treatment received after 12months, against 73% in the norethindrone acetate group.

34

GnRH analoguesThese drugs exert a negative feedback effect on the pituitary, causing hypogonadotrophichypogonadism that leads to amenorrhea and anovulation, which account for their therapeutic effect.This inhibitory effect is reversible.35,36These analogues cannot be administered orally because theyare readily destroyed by the digestive process, but they may be given parenterally subcutaneously, intramuscularly, by nasal spray, or in vaginal pessaries.

35 Efficacy of GnRH

analogues is equivalent to that of danazol for promoting regression of implants and reducing pain,with fewer adverse effects.

36 A study assessing changes in endometriosis-associated pain and

quality of life during the stimulatory phase of GnRH analogue therapy showed that, after 2 weeks,visual analog scale pain scores were higher in the treatment group. After 4 weeks, women treatedwith leuprorelin had a significant improvement in pain. Regarding quality of life, measured with theSF-36 instrument, there was no significant difference between groups.

37

LeuprorelinIn comparison with placebo, dysmenorrhea, pelvic pain, and pelvic tenderness respondedsignificantly to leuprorelin treatment.

38,39A placebo-controlled clinical trial comparing nafarelin and

leuprorelin showed that the drugs were more effective than placebo in relieving pain, with nodifferences between active treatment groups.

40,41 Treatment with leuprorelin (3.75 mg) compared

with a 3-month expectant management in 89 women with symptomatic endometriosis stage III-IVshowed no statistically significant differences between GnRH and control groups regardingpregnancy rates (33 vs. 40%), moderate/severe pain recurrence rates (23 vs. 24%), and cumulativepain recurrence rates at 18 months (23 vs. 29%).

42

In an open clinical trial comparing leuprorelin acetate (3.75 mg, every 28 days) with danazol (200mg, 3 times daily, for 24 weeks), endometriosis symptoms significantly improved in both treatmentgroups. Hypoestrogenic side effects (hot flushes) were more common in patients receivingleuprorelin, but anabolic/androgenic effects (weight gain and acne) were more common in thosereceiving danazol.

43

Goserelin

A study comparing goserelin (3.6 mg, subcutaneously, every 28 days) with danazol (200 mg, 3times daily) showed that both treatments were equally effective in reducing AFS scores (adhesions,implants), pelvic symptoms, and physical examination findings.

44-46 Improvements could still be

observed 6 months after drug withdrawal.45

TriptorelinIn a randomized clinical trial comparing triptorelin (3.75 mg, intramuscularly, every 28 days) withplacebo, pain scores and extent of endometriosis were significantly reduced in the actively treatedgroup (50% reduction in the triptorelin group vs. 17% increase in the placebo group).

47An open

randomized clinical trial, with a small sample, showed no significant differences between groupsregarding pelvic pain persistence or recurrence assessed by the verbal rating scale, endometriomarelapse, or pregnancy rates.

48Curves of pain recurrence and pregnancy during a 5-year follow-up

did not show significant differences between treatment and intervention groups.There are only a few clinical trials comparing different GnRH analogues in the treatment ofendometriosis. Results have shown no differences between GnRH analogues in terms of symptomimprovement in patients with endometriosis. A randomized clinical trial comparing nafarelin andleuprorelin found no significant improvement in quality of life scores at 3 and 6 months.

41

A randomized, double-blind study comparing treatment for 3 months with triptorelin (T) andleuprorelin (L) showed no significant differences in LH, FSH, estradiol, liver function, and lipid profilebiochemical parameters.

49Likewise, no differences were observed in the onset of hypoestrogenic

symptoms and vaginal bleeding. In that same study, during the crossover phase, the drugs wereevaluated for an additional 3-month period. Eight weeks after the last dose of the analogue, morepatients in the L/T group (80%) than in the T/L group (51.9%) had abnormally low estradiol and LH


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levels. Time to the return of menstruation was significantly longer in the L/T group than in the T/Lgroup; however, because of a change in the sequence of drugs, it was not possible to concludewhether the prolonged action observed was due to the last drug used or to the sequence adopted.In an open randomized clinical trial comparing goserelin and nafarelin,

50 both drugs significantly

reduced pain scores from baseline, with no significant differences between groups. There were nosignificant differences between groups in pain scores or adverse events (hot flushes, headache,sweating, vaginal dryness, vaginal bleeding).In summary, GnRH analogues are similar in terms of efficacy and effectiveness. Although nafarelinshows similar efficacy to that of the remaining GnRH analogues, this drug does not provide furthereffectiveness and its dosage requirements hinder adherence to treatment. Therefore, nafarelintherapy was not included in this CPG.

Add-back therapyAdd-back therapy (a combination of hormonal or nonhormonal treatment with GnRH analogues) isindicated to reduce adverse effects of GnRH analogues hypoestrogenic effects, vasomotorsymptoms, and bone loss. The most commonly used hormone replacement therapies (HRT)include progestagens, estrogens, or a combination of progestagens and estrogens.A study comparing goserelin with or without HRT (17-beta estradiol 2 mg + norethisterone acetate 1mg) showed that the addition of HRT resulted in fewer hot flushes and alterations in libido and lessvaginal dryness. Add-back therapy does not reduce treatment efficacy (pain relief and reduction of

endometriotic implants) and provides substantial improvement in hypoestrogenic symptoms51andquality of life.

52 A meta-analysis comparing tibolone and medroxyprogesterone acetate (100

mg/day) with norethisterone, in a combination of estradiol (2 mg) and norethisterone (1 mg/day),showed no differences between various regimens in relation to pain relief. There was significantimprovement in adverse effects hot flushes, vaginal dryness, and decreased bone loss.

53-57

Another study observed an earlier return of dysmenorrhea, pelvic pain, and pelvic nodules tobaseline levels in the group receiving add-back therapy with a higher dose of estrogen(norethindrone acetate 5 mg/day + conjugated estrogens 1.25 mg/day) than in the remaininggroups (placebo, norethindrone acetate 5 mg/day, and norethindrone acetate 5 mg/day +conjugated estrogens 0.625 mg/day).

58 Similarly, a randomized clinical trial, with a small sample,

comparing the use of GnRH analogues with placebo or combined with ethinyl estradiol (20 mg) anddesogestrel (0.15 mg) showed significant improvements in dysmenorrhea and pelvic pain in bothgroups. The GnRH + placebo group had significantly higher serum calcium levels and significantly

higher loss of BMD.59

In a clinical trial,

60133 women with a surgical diagnosis of endometriosis and recurrent pelvic pain,

dysmenorrhea, or dyspareunia were randomized into 3 treatment groups: group A) leuprorelinacetate (11.25 mg, every 3 months) + transdermal estrogen and norethindrone (5 mg, orally); groupB) leuprorelin acetate (11.25 mg, every 3 months); and group C) OC E/P (ethinyl estradiol 0.03 mg+ gestodene 0.75 mg). Patients treated either with GnRH analogue alone or GnRH analogue plusadd-back therapy showed a higher reduction of pelvic pain, dysmenorrhea, and dyspareunia thanpatients treated with OC. Patients treated with add-back therapy showed better quality of lifescores, as assessed by the SF-36, lower bone loss, and fewer episodes of hot flushes than patientstreated with GnRH analogue alone, but with scores similar to those of patients treated with OC.In a meta-analysis

61 including 15 studies and 910 women with a laparoscopic diagnosis of

endometriosis, add-back therapy with progestagen alone did not improve BMD after a 6-monthfollow-up period (95%CI -0.21 to 0.52). When add-back therapy with estrogen alone or estrogen +progesterone was adopted, there was a significant increase in BMD after 6 months (95%CI -0.77 to-0.21) and after 12 months (95%CI -1.02 to -0.10). This result was also demonstrated in arandomized double-blind clinical trial

62 comparing leuprorelin acetate (3.75 mg, monthly), which,

after the third injection, was used in combination with promegestone (0.5 mg + placebo (PP)), withleuprorelin acetate (3.75 mg, monthly), which, after the third injection, was used in combination withestradiol (2 mg + promegestone (EP)). At month 12, BMD changes were higher in the group withprogestagens and were prevented in the group with estrogens. A study with a small sample alsoobserved that the number of endometriotic implants was significantly reduced in both groups, withno significant differences between groups.

63BMD decreased by 5.02% in the group that received

goserelin + placebo and increased by 0.18% in the group that received add-back HRT. The


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Kupperman Index score decreased by 75, 129, and 113% in the placebo group, after 4, 12, and 24months, respectively, with a significant difference between groups at the end of treatment.Monthly goserelin acetate without HRT was compared with estradiol (2 mg/day combined withnorethisterone acetate 1 mg/day, both orally, for 2 years), and no differences were observedbetween groups in relation to BMD at the end of treatment. After a 6-year follow-up period, meanBMD was 87.2% in the group with HRT and 86.8% in the group without HRT. However, sample sizewas small and the study was underpowered to detect differences.

64

Only a study with a small sample of 13 patients, in which estradiol (1 mg/day, orally, in 6 patients )was combined with leuprorelin acetate, showed a trend toward increasing pain with estrogen add-back therapy. Hot flushes were less severe in the estradiol group. However, differences observedbetween groups did not reach statistical significance.

65

Other treatments, such as levonorgestrel-releasing intrauterine device,66-69

pentoxifylline,70,71

dienogest,

72,73 anastrozole,

74 lynestrenol,

75 Chinese herbal medicine,

76,77 infliximab,

78 etonogestrel

implant,79

and raloxifene,80

have been tested for endometriosis, but evidence is deemed insufficientto justify their recommendation.

8.2 SURGICAL TREATMENTSurgical treatment is indicated in the following cases: presence of severe or disabling symptoms;unresponsiveness to empirical treatment wit oral contraceptives or progestagens; endometrioma;distortion of pelvic anatomy; adhesions; intestinal or urinary tract obstruction; and endometriosis-

associated infertility.1,25 Surgical interventions may be classified as conservative or definitivesurgery.

Conservative surgeryThis procedure involves the destruction of endometriotic implants and removal of adhesions withconsequent restoration of pelvic anatomy. There is a significant degree of pain relief at 6 monthsafter laparoscopic surgery in patients with minimal, mild, or moderate endometriosis in comparisonto expectant management (OR 4.97; 95%CI 1.85 to 13.39).

81

Definitive surgeryThis procedure involves hysterectomy with or without oophorectomy (according to the age of thepatient). It is indicated in the presence of severe disease, persistence of disabling symptoms afterdrug therapy or conservative surgery, other pelvic diseases with indication for hysterectomy, and

cases in which there is no desire for pregnancy. Hysterectomy with bilateral salpingo-oophorectomyand resection of all endometriotic implants resulted in cure in 90% of cases (non-controlledstudies).

2

A randomized clinical trial showed greater efficacy of laparoscopic surgery (ablation of implants,adhesiolysis, and uterosacral nerve ablation) compared with diagnostic laparoscopy, with significantcontinued pain relief at 1 year after treatment in up to 90% of patients.

82 Regarding infertility

associated with minimal or mild endometriosis, a study of 341 patients showed that laparoscopicsurgery (resection or surgical ablation of implants) increased the cumulative probability ofpregnancy.

18A study with a smaller sample failed to reproduce these results.

83

8.3 ADD-BACK THERAPYHormonal suppression prior to surgery may reduce the need for surgical dissection, but it cannotprolong disease-free interval, increase fertility rates, or reduce recurrence rates.

20

The addition of low-dose danazol (100 mg/day) after combined surgical and GnRH analoguetherapy was effective in improving painful symptoms and managing pain for 12 and 24 months.84However, short-term (3 months) danazol therapy showed no benefits in a study of patients withstage III-IV endometriosis.

85 A prospective, non-controlled study evaluating the efficacy of

postoperative administration of oral contraceptives found no differences in the recurrence rate ofendometriosis symptoms or endometrioma formation.

86 Two studies analyzing postoperative

administration of GnRH analogues showed better pain management and delayed recurrence ofendometriosis in a follow-up period longer than 12 months compared to placebo, but with noimprovement in fertility rates.

17,87Other clinical trials, with small sample size, testing short-term (3

months) GnRH analogue therapy showed no benefit for pain relief or fertility rates.16,42,48


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Evidence supporting the benefits of add-back therapy is not clear, and drug therapy is thereforerestricted to patients with recurrent symptoms after surgery.A meta-analysis

88included 11 studies that evaluated the effectiveness of medical treatment before

and after surgery in women with endometriosis. A randomized clinical trial comparing surgicaltreatment alone with pre-surgical use of medical therapy showed significant improvement in AFSscores in the group receiving drug therapy. Regarding post-surgical hormonal suppression, 8randomized clinical trials were included and showed no benefit for the outcomes of pain orpregnancy rates but a significant improvement in disease recurrence. A randomized clinical trialshowed no significant difference between pre- and postoperative hormonal suppression betweengroups for the outcomes of pelvic pain, pelvic nodules, or dyspareunia. When comparing hormonalsuppression before and after surgery with surgery alone, a randomized clinical trial showed nodifference between groups regarding AFS scores or pregnancy rates. In that meta-analysis, there isinsufficient evidence to conclude that hormonal suppression in combination with surgery isassociated with a significant benefit in the treatment of endometriosis.

8.4 DRUGS Oral contraceptives: formulations available in the Brazilian Public Health System Danazol: capsules of 50, 100, and 200 mg GnRH analogues Goserelin: injection with a single dose of 3.6 or 10.8 mg

Leuprorelin: vials of 3.75 or 11.25 mg Triptorelin: vials of 3.75 or 11.25 mg

8.5 ADMINISTRATION Oral contraceptives: administration according to formulations available in the Brazilian PublicHealth System Danazol: 200 mg, orally, 2 times daily; the dose may be increased up to 400 mg, 2 times daily GnRH analogues Goserelin: 3.6 mg, subcutaneously, monthly or 10.8 mg every 3 months Leuprorelin: 3.75 mg, intramuscularly, monthly or 11.25 mg every 3 months Triptorelin: 3.75 mg, intramuscularly, monthly or 11.25 mg every 3 months

8.6 EXPECTED BENEFITS OF CLINICAL TREATMENT

Pain relief (usually within 3 weeks) Regression of endometriotic nodules (usually within 6 weeks)

8.7 TREATMENT DURATION CRITERIA FOR DISCONTINUATIONThe majority of studies

26,40,41,45,51,89,90have treated patients for a 6-month period. The recommended

duration of treatment is 3-6 months. Patients who have used GnRH analogues for a 6-monthperiod, but still have pain symptoms or recurrence of endometriosis-related pain, should be referredto a specialized service.

9 MONITORING Danazol: platelet count every 4-6 months (thrombocytosis/thrombocytopenia were observed).Patients on concomitant use of danazol and carbamazepine may show a significant increase incarbamazepine levels resulting in toxicity. GnRH analogues: patients referred to a specialized service receiving GnRH analogues for morethan 6 months should be assessed for risk of osteoporosis. Medroxyprogesterone: due to central inhibition of FSH release, BMD should be assessed every 2years to rule out osteoporosis.

10 POST-TREATMENT FOLLOW-UPPatients should be reassessed every 6 months for withdrawal of danazol and GnRH analogues.Requests for retreatment or treatment for longer periods of time are covered in the section SpecialCases. Patients who have used escalated doses (oral contraceptives, progestagens, GnRHanalogues), but still have pain symptoms or recurrence of endometriosis-related pain should be


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referred to a specialized service for reevaluation. Retreatment in these cases does not require newdiagnostic tests, only a confirmation of symptoms present and absence of treatment responsereported in writing by a physician.

11 REGULATION/CONTROL/MANAGER ASSESSMENTPatients with endometriosis should be referred to specialized gynecology services for properdiagnosis and subsequent inclusion in the appropriate CPG.Aspects such as criteria for inclusion and exclusion of patients in this CPG, treatment duration andmonitoring, regular evaluation of the doses prescribed and dispensed, adequacy of drug therapy,and post-treatment follow-up should be observed.Treatment with danazol or GnRH analogues will only be prescribed if patients are diagnosedaccording to the criteria listed under Diagnosis and Inclusion Criteria and if patients areunresponsive to previous treatment with OC or progestagens, as established and reported in writingby a physician.

12 INFORMED CONSENT AND LIABILITY FORMIt is a legal requirement that patients or their legal guardians be informed of the potential risks,benefits, and adverse effects associated with the pharmacological treatment recommended in thisguideline.Informed consent should be obtained with the appropriate form when prescribing drugs included in

the Specialized Program for Pharmaceutical Assistance.

13 REFERENCES1. European Society for Human Reproduction and Embryology (ESHRE). The ESHRE Guideline for theDiagnosis and Treatment of Endometriosis [Internet]. Grimbergen: ESHRE; [updated 2007 Jun 30; cited 2009Oct 9]. Available from: http://guidelines.endometriosis.org.

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20. Schenken RS. Overview of the treatment of endometriosis [Internet]. Waltham (MA): UpToDate; 2009[cited 2010 May 17]. Available from: http://www.uptodate.com/patients/content/topic.do?topicKey=~ie7xLcpH_GU9HJi&selectedTitle=1~150.

21. Harada T, Momoeda M, Taketani Y, Hoshiai H, Terakawa N. Low-dose oral contraceptive pill fordysmenorrhea associated with endometriosis: a placebo-controlled, double-blind, randomized trial. Fertil Steril.2008;90(5):1583-8. Epub 2007 Dec 27.22. Sesti F, Pietropolli A, Capozzolo T, Broccoli P, Pierangeli S, Bollea MR, et al. Hormonal suppression

treatment or dietary therapy versus placebo in the control of painful symptoms after conservative surgery forendometriosis stage III-IV. A randomized comparative trial. Fertil Steril. 2007;88(6):1541-7. Epub 2007 Apr 16.23. Vercellini P, Trespidi L, Colombo A, Vendola N, Marchini M, Crosignani PG. A gonadotropin-releasinghormone agonist versus a low-dose oral contraceptive for pelvic pain associated with endometriosis. Fertil

Steril. 1993;60(1):75-9.24. Parazzini F, Di Cintio E, Chatenoud L, Moroni S, Ardovino I, Struzziero E, et al. Estroprogestin vs.gonadotrophin agonists plus estroprogestin in the treatment of endometriosis-related pelvic pain: a randomizedtrial. Gruppo Italiano per lo Studio dellEndometriosi. Eur J Obstet Gynecol Reprod Biol. 2000;88(1):11-4.25. Reddy S, Rock JA. Treatment of endometriosis. Clin Obstet Gynecol. 1998;41(2):387-92.26. Selak V, Farquhar C, Prentice A, Singla A. Danazol for pelvic pain associated with endometriosis.Cochrane Database Syst Rev. 2007;(4):CD000068.27. Miller JD, Shaw RW, Casper RF, Rock JA, Thomas EJ, Dmowski WP, et al. Historical prospective cohort

study of the recurrence of pain after discontinuation of treatment with danazol or a gonadotropin-releasinghormone agonist. Fertil Steril. 1998;70(2):293-6.28. Wong AY, Tang L. An open and randomized study comparing the efficacy of standard danazol and

modified triptorelin regimens for postoperative disease management of moderate to severe endometriosis.Fertil Steril. 2004;81(6):1522-7.29. Prentice A, Deary AJ, Bland E. Progestagens and anti-progestagens for pain associated withendometriosis. Cochrane Database Syst Rev. 2000;(2):CD002122.30. Vercellini P, De Giorgi O, Oldani S, Cortesi I, Panazza S, Crosignani PG. Depot medroxyprogesteroneacetate versus an oral contraceptive combined with very-low-dose danazol for long-term treatment of pelvic

pain associated with endometriosis. Am J Obstet Gynecol. 1996;175(2):396-401.31. Schlaff WD, Carson SA, Luciano A, Ross D, Bergqvist A. Subcutaneous injection of depotmedroxyprogesterone acetate compared with leuprolide acetate in the treatment of endometriosis-associatedpain. Fertil Steril. 2006;85(2):314-25.32. Crosignani PG, Luciano A, Ray A, Bergqvist A. Subcutaneous depot medroxyprogesterone acetate versusleuprolide acetate in the treatment of endometriosis-associated pain. Hum Reprod. 2006;21(1):248-56. Epub2005 Sep 21.33. Razzi S, Luisi S, Ferretti C, Calonaci F, Gabbanini M, Mazzini M, et al. Use of a progestogen onlypreparation containing desogestrel in the treatment of recurrent pelvic pain after conservative surgery for

endometriosis. Eur J Obstet Gynecol Reprod Biol. 2007;135(2):188-90. Epub 2006 Sep 11.34. Vercellini P, Pietropaolo G, De Giorgi O, Pasin R, Chiodini A, Crosignani PG. Treatment of symptomaticrectovaginal endometriosis with an estrogen-progestogen combination versus low-dose norethindrone acetate.Fertil Steril. 2005;84(5):1375-87.35. Moghissi KS. A clinicians guide to the use of gonadotropin-releasing hormone analogues in women.Medscape Womens Health. 2000;5(1):5.36. Prentice A, Deary AJ, Goldbeck-Wood S, Farquhar C, Smith SK. Gonadotrophin-releasing hormone

analogues for pain associated with endometriosis. Cochrane Database Syst Rev. 2000;(2):CD000346.37. Miller JD. Quantification of endometriosis-associated pain and quality of life during the stimulatory phase ofgonadotropin-releasing hormone agonist therapy: a double-blind, randomized, placebo-controlled trial. Am JObstet Gynecol. 2000;182(6):1483-8.38. Dlugi AM, Miller JD, Knittle J. Lupron depot (leuprolide acetate for depot suspension) in the treatment ofendometriosis: a randomized, placebo-controlled, double-blind study. Lupron Study Group. Fertil Steril.1990;54(3):419-27.39. Ling FW. Randomized controlled trial of depot leuprolide in patients with chronic pelvic pain and clinically

suspected endometriosis. Pelvic Pain Study Group. Obstet Gynecol. 1999;93(1):51-8.40. Agarwal SK, Hamrang C, Henzl MR, Judd HL. Nafarelin vs. leuprolide acetate depot for endometriosis.Changes in bone mineral density and vasomotor symptoms. Nafarelin Study Group. J Reprod Med.1997;42(7):413-23.41. Zhao SZ, Kellerman LA, Francisco CA, Wong JM. Impact of nafarelin and leuprolide for endometriosis onquality of life and subjective clinical measures. J Reprod Med. 1999;44(12):1000-6.42. Busacca M, Somigliana E, Bianchi S, De Marinis S, Calia C, Candiani M, et al. Post-operative GnRHanalogue treatment after conservative surgery for symptomatic endometriosis stage III-IV: a randomizedcontrolled trial. Hum Reprod. 2001;16(11):2399-402.


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43. Rotondi M, Labriola D, Rotondi M, Ammaturo FP, Amato G, Carella C, et al. Depot leuprorelin acetateversus danazol in the treatment of infertile women with symptomatic endometriosis. Eur J Gynaecol Oncol.2002;23(6):523-6.

44. Goserelin depot versus danazol in the treatment of endometriosis the Australian/New Zealand experience.Aust N Z J Obstet Gynaecol. 1996;36(1):55-60.45. Shaw RW. An open randomized comparative study of the effect of goserelin depot and danazol in thetreatment of endometriosis. Zoladex Endometriosis Study Team. Fertil Steril. 1992;58(2):265-72.

46. Rock JA, Truglia JA, Caplan RJ. Zoladex (goserelin acetate implant) in the treatment of endometriosis: arandomized comparison with danazol. The Zoladex Endometriosis Study Group. Obstet Gynecol.1993;82(2):198-205.47. Bergqvist A, Bergh T, Hogstrm L, Mattsson S, Nordenskjld F, Rasmussen C. Effects of triptorelin versus

placebo on the symptoms of endometriosis. Fertil Steril. 1998;69(4):702-8.48. Loverro G, Carriero C, Rossi AC, Putignano G, Nicolardi V, Selvaggi L. A randomized study comparingtriptorelin or expectant management following conservative laparoscopic surgery for symptomatic stage III-IVendometriosis. Eur J Obstet Gynecol Reprod Biol. 2008;136(2):194-8. Epub 2006 Dec 18.49. Cheung TK, Lo KW, Lam CW, Lau W, Lam PK. A crossover study of triptorelin and leuprorelin acetate.Fertil Steril. 2000;74(2):299-305.50. Bergqvist A; SCANDET Group. A comparative study of the acceptability and effect of goserelin andnafarelin on endometriosis. Gynecol Endocrinol. 2000;14(6):425-32.

51. Kiilholma P, Tuimala R, Kivinen S, Korhonen M, Hagman E. Comparison of the gonadotropin-releasinghormone agonist goserelin acetate alone versus goserelin combined with estrogen-progestogen add-backtherapy in the treatment of endometriosis. Fertil Steril. 1995;64(5):903-8.

52. Bergqvist A, Theorell T. Changes in quality of life after hormonal treatment of endometriosis. Acta ObstetGynecol Scand. 2001;80(7):628-37.53. Hornstein MD, Surrey ES, Weisberg GW, Casino LA. Leuprolide acetate depot and hormonal add-back inendometriosis: a 12-month study. Lupron Add-Back Study Group. Obstet Gynecol. 1998;91(1):16-24.54. Mkrinen L, Rnnberg L, Kauppila A. Medroxyprogesterone acetate supplementation diminishes thehypoestrogenic side effects of gonadotropin-releasing hormone agonist without changing its efficacy in

endometriosis. Fertil Steril. 1996;65(1):29-34.55. Moghissi KS, Schlaff WD, Olive DL, Skinner MA, Yin H. Goserelin acetate (Zoladex) with or withouthormone replacement therapy for the treatment of endometriosis. Fertil Steril. 1998;69(6):1056-62.56. Taskin O, Yalcinoglu AI, Kucuk S, Uryan I, Buhur A, Burak F. Effectiveness of tibolone on hypoestrogenicsymptoms induced by goserelin treatment in patients with endometriosis. Fertil Steril. 1997;67(1):40-5.57. Cheung TH, Lo KW, Yim SF, Lam C, Lau E, Haines C. Dose effects of progesterone in add-back therapyduring GnRHa treatment. J Reprod Med. 2005;50(1):35-40.58. Surrey ES, Hornstein MD. Prolonged GnRH agonist and add-back therapy for symptomatic endometriosis:long-term follow-up. Obstet Gynecol. 2002;99(5 Pt 1):709-19.

59. Gnoth CH, Gdtke K, Freundl G, Godehardt E, Kienle E. Effects of add-back therapy on bone mineraldensity and pyridinium crosslinks in patients with endometriosis treated with gonadotropin-releasing hormoneagonists. Gynecol Obstet Invest. 1999;47(1):37-41.60. Zupi E, Marconi D, Sbracia M, Zullo F, De Vivo B, Exacustos C, et al. Add-back therapy in the treatment ofendometriosis-associated pain. Fertil Steril. 2004;82(5):1303-8.61. Sagsveen M, Farmer JE, Prentice A, Breeze A. Gonadotrophin-releasing hormone analogues forendometriosis: bone mineral density. Cochrane Database Syst Rev. 2003;(4):CD001297.

62. Fernandez H, Lucas C, Hedon B, Meyer JL, Mayenga JM, Roux C. One year comparison between twoadd-back therapies in patients treated with a GnRH agonist for symptomatic endometriosis: a randomizeddouble-blind trial. Hum Reprod. 2004;19(6):1465-71. Epub 2004 Apr 22.63. Franke HR, van de Weijer PH, Pennings TM, van der Mooren MJ. Gonadotropin-releasing hormoneagonist plus add-back hormone replacement therapy for treatment of endometriosis: a prospective,randomized, placebo-controlled, double-blind trial. Fertil Steril. 2000;74(3):534-9.64. Pierce SJ, Gazvani MR, Farquharson RG. Long-term use of gonadotropin-releasing hormone analogs andhormone replacement therapy in the management of endometriosis: a randomized trial with a 6-year follow-up.

Fertil Steril. 2000;74(5):964-8.65. Hurst BS, Gardner SC, Tucker KE, Awoniyi CA, Schlaff WD. Delayed oral estradiol combined withleuprolide increases endometriosis-related pain. JSLS. 2000;4(2):97-101.66. Abou-Setta AM, Al-Inany HG, Farquhar CM. Levonorgestrel-releasing intrauterine device (LNG-IUD) forsymptomatic endometriosis following surgery. Cochrane Database Syst Rev. 2006;(4):CD005072.67. Petta CA, Ferriani RA, Abrao MS, Hassan D, Rosa E Silva JC, Podgaec S, et al. Randomized clinical trialof a levonorgestrel-releasing intrauterine system and a depot GnRH analogue for the treatment of chronicpelvic pain in women with endometriosis. Hum Reprod. 2005;20(7):1993-8. Epub 2005 Mar 24.


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Informed Consent and Liability FormDanazol, Goserelin, Leuprorelin, and Triptorelin

I, ____________________________________________________ (name of patient), declare that Ihave been clearly informed of the benefits, risks, contraindications, and major adverse effectsassociated with the use of danazol, goserelin, leuprorelin, and triptorelin, indicated for the

treatment of endometriosis.The medical terms have been explained and all my questions were answered by the physician, Dr._______________________________________________________ (name of the prescribingphysician).Therefore, I declare that I have been clearly informed that the drug that I will receive may result inthe following improvements: pain relief; reduction of endometrial nodules.I have also been clearly informed of the following contraindications, potential adverse effects, andrisks of using this drug: contraindicated in pregnancy or in women planning to become pregnant; contraindicated in women who are breastfeeding; adverse effects of danazol common: menstrual disorders, weight gain, hot flushes; less

common: swelling, dark urine, fatigue, drowsiness, acne, oily hair and skin, hair loss, voice change,enlarged clitoris; rare: adenoma, cataracts, eosinophilia, hepatic dysfunction, pancreatitis,increased intracranial pressure manifested as headache, nausea and vomiting, leukocytosis, skinrash, Stevens-Johnson syndrome, thrombocytopenia, and photosensitivity; adverse effects of goserelin common: hot flushes, menstrual disorders; less common: blurredvision, decreased libido, fatigue, headache, nausea, vomiting, difficulty sleeping, weight gain,vaginitis; rare: angina or myocardial infarction, and thrombophlebitis; adverse effects of leuprorelin common: hot flushes, diarrhea, menstrual disorders; less common:cardiac arrhythmias, palpitation; rare: dry mouth, thirst, appetite changes, anxiety, nausea,vomiting, personality disorders, memory disorders, decreased libido, weight gain, difficulty sleeping,delirium, body aches, hair loss, and eye problems; adverse effects of triptorelin common: hot flushes, bone pain, injection site pain, hypertension,headache; less common: leg pain, fatigue, vomiting, and insomnia; rare: dizziness, diarrhea, urinaryretention, urinary tract infection, anemia, and pruritus; contraindicated in cases of hypersensitivity (allergy) to the drug; the risk of adverse effects increases with overdose.I am aware that this drug can be used only by myself, and I commit myself to returning the drug if Ido not want or cannot use it, or if treatment is discontinued. I am also aware that I will continue toreceive medical care even if I quit using the drug.I authorize the Ministry of Health and the Departments of Health Care to make use of informationconcerning my treatment, provided that my privacy is protected.My treatment consists of the following drug(s):!danazol!goserelin!leuprorelin!triptorelin

Place: Date:

Patient's name:

National Health Card:

Name of legal guardian:

Identification document of legal guardian:

_____________________________________Signature of patient or legal guardian

Physician in charge: License number: State:


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___________________________Signature and stamp of physician

Date: ___________________

Note: This Form is required when requesting drugs included in the Specialized Program forPharmaceutical Assistance and should be completed in duplicate: one copy should be filed in thepharmacy, the other delivered to the user or their legal guardian.


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Flow Chart of Medical TreatmentEndometriosis

[arquivo anexo]


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Dispensing Flow Chart: Danazol, Goserelin, Leuprorelin, and TriptorelinEndometriosis

[arquivo anexo]


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Drug Therapy Registration FormEndometriosis

1 Patient DataName: _________________________________________________________________________National Health Card: ___________________________ ID: _______________________________

Name of caregiver: _______________________________________________________________National Health Card: ________________________________ ID: __________________________Sex: !Male !Female DOB: ___ / ___ / ____ Age: ____ Weight: _______ Height: _____________Address: _______________________________________________________________________Telephones: _____________________________________________________________________Primary physician: _________________________________________ License number: ________Telephones: _____________________________________________________________________

2 Drug Therapy Evaluation2.1 What treatments have been previously employed to treat endometriosis? When?_____________________________________________________________________________________________________________________________________________________________________________________________________________________________________________

2.2 Patient has other diagnosed diseases:!no!yes "Please describe: __________________________________________________________

2.3 Patient uses other drugs*: !no !yes "Please describe:

Trade name Generic name Total dose/day and route Start date Prescription!no !yes!no !yes!no !yes!no !yes

* Concomitant use of danazol and carbamazepine may result in carbamazepine toxicity.

2.4 Patient has had allergic reactions to drugs:!no!yes "What types of reactions? To what drugs? _______________________________________

3 Treatment Monitoring

Laboratory Tests for Danazol Therapy

Baseline 6th month 12th month

Scheduled date

Date

Platelets

3.1 Patient presented abnormal platelet count:

no "Dispense drugyes "Dispense drug and refer patient to the primary physician

3.2 Patient presented symptoms suggestive of adverse events (fill in the Adverse Event Record):no "Dispense drugyes "Go to question 3.3

3.3 Patient needs to be assessed by the primary physician regarding the adverse event:no "Dispense drug


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yes "Dispense drug and refer patient to the primary physician

Adverse Event RecordDate of interview Adverse event *Intensity #Management strategy

Main adverse reactions previously reported:Danazol: menstrual disorders, weight gain, hot flushes, swelling, dark urine, fatigue, drowsiness,acne, oily hair and skin, alopecia, voice change, enlarged clitoris, headache, nausea and vomiting,skin rash, photosensitivityGoserelin: hot flushes, menstrual disorders, blurred vision, decreased libido, fatigue, headache,nausea, vomiting, insomnia, weight gain, vaginitis, chest pain, leg pain

Leuprorelin: hot flushes, menstrual disorders, cardiac arrhythmias, palpitation, dry mouth, thirst,appetite changes, anxiety, nausea, vomiting, personality disorders, memory disorders, decreasedlibido, weight gain, insomnia, delirium, myalgia, alopecia, and eye problemsTriptorelin: hot flushes, bone pain, injection site pain, hypertension, headache, leg pain, fatigue,vomiting, insomnia, dizziness, diarrhea, urinary retention, urinary tract infection, anemia, pruritus* Intensity: (Mi) mild; (Mo) moderate; (S) severe# Management strategy: (P) pharmacological (indication of over-the-counter drugs); (NP) non-pharmacological (dietary practices, water intake, exercise, others); (RP) referral to the primaryphysician; (OT) other (please describe)

Dispensing Record1stmonth

2ndmonth

3rdmonth

4thmonth

5thmonth

6thmonth

DateTrade nameBatch/Expiration datePrescribed doseAmount dispensedNext dispensation date (medicalopinion required: yes/no)Pharmacist in charge/licensenumberNotes

7thmonth

8thmonth

9thmonth

10thmonth

11thmonth

12thmonth

DateTrade name

Batch/Expiration datePrescribed doseAmount dispensedNext dispensation date (medicalopinion required: yes/no)Pharmacist in charge/licensenumber


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Notes* GnRH analogues may be dispensed every 3 months (for 3-month drug formulations).


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Do not use other drugs without the doctor's consent or without obtaining guidance from a healthprofessional.

7 Other important information Goserelin, leuprorelin, and triptorelin may be used once a month or every 3 months. Therefore,check the drug formulation that you received to avoid using the drug at intervals different than those

recommended. In case of doubt, consult a health professional (doctor, nurse, or pharmacist of theBrazilian Public Health System).

8 Laboratory tests The performance of laboratory tests ensures an accurate evaluation of the effect of the drug onyour body. In some cases, dose adjustments or even discontinuation of treatment may benecessary.

9 To continue receiving the drug Return to the pharmacy every month, with the following documents:$Current prescription$National Health Card or ID!Tests for danazol: platelet count every 4-6 months

10 In case of doubt If you have any questions that have not been addressed in this guide, consult the doctor orpharmacist of the Brazilian Public Health System before taking any action.

11 Additional information_______________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________

If, for any reason, you do not use the drug(s) received,return it to the pharmacy of the Brazilian Public Health System.

clinical practice guideline endometriosis

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