Estrogen products can be used to treat a variety of reasons, including birth control and treatment of menopause. Menopause, or cessation of menstrual periods, is a natural process that all women experience with increasing age. Menopause indicates the end of a woman’s fertility period, since the ovaries stop releasing eggs and produce smaller amounts of hormones, including estrogen. Menopause most commonly occurs in women between the ages of 45 and 55.

Some women who reach menopause are asymptomatic. However, some women experience a variety of symptoms associated with their menopause.These include vasomotor symptoms such as hot flashes, sweating, irritability, difficulty concentrating, and insomnia. Other symptoms include vaginal dryness and itching.

Menopausal hormone replacement therapy (HRT) is the mainstay of treatment for these women. The purpose of HRT is to replace the hormones, such as estrogen and progesterone, which women are lacking in order to alleviate the menopausal symptoms they are experiencing. Estrogen may be replaced alone or in combination with progesterone.

Bioidentical hormones are plant-derived hormones that are structurally identical to those produced in the body. The US Food and Drug administration (FDA), however, has recognized the term “bioidentical” as a marketing term that has no scientific basis. These types of hormones are compounded in pharmacies according to the healthcare provider’s instructions and are not regulated by the FDA. They have no official labeling and do not have to include contraindications or warnings. These preparations lack basic pharmacokinetic data and may include non-government approved or monitored hormones which some women may not be able to tolerate. Many bioidentical hormone replacement therapies have not had any significant testing for clinical efficacy, safety, purity, potency, or quality. The variability in both bioavailability and bioactivity between products makes both underdosing and overdosing possible.

The FDA has stated that some compounding pharmacies have made false and misleading claims regarding the safety and efficacy of bioidentical hormonal therapy. The FDA conducted analysis testing over a 6 month period of 29 internet ordered bioidentical hormone therapies. They found that 34% of the preparations failed at least one standard quality test, compared to the 2% failure rate of FDA approved drug therapies.

There are various routes of administration of these bioidentical hormones, including subcutaneous implantation, oral, intrauterine system, and transdermal system.

CDC created U.S. Medical Eligibility Criteria for Contraceptive Use, 2010, from guidance developed by the World Health Organization (WHO) and finalized the recommendations after consultation with a group of health professionals who met in Atlanta, Georgia, during February 2009. This guidance comprises recommendations for the use of specific contraceptive methods by women and men who have certain characteristics or medical conditions. This guideline should be considered when prescribing oral contraceptives.

Long-acting reversible contraceptives (LARC) are a safe and highly effective method of family planning that provide contraception for an extended period without requiring member action (or compliance). They include intrauterine devices (IUDs) and subdermal contraceptive implants. Both methods are reversible and can be removed at any time if member chooses.

[INFORMATIONAL NOTE: The FDA-approved package inserts have the following BLACK BOX WARNINGS:

Depo-Provera- Women who use medroxyprogesterone acetate injection may lose calcium stored in their bones, and thus significant bone mineral density. Bone loss is greater with increasing duration of use and may not be completely reversible. It is unknown if use of medroxyprogesterone acetate during adolescence or early adulthood, a critical period of bone accretion, will reduce peak bone mass and increase the risk for osteoporotic fracture in later life. Medroxyprogesterone acetate should be used as a long-term birth control method (eg, longer than 2 years) only if other birth control methods are inadequate

Nuvaring and Ortho Evra - Cigarette smoking increases the risk of serious cardiovascular side effects from combination hormonal contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes per day) and is quite marked in women over 35 years of age. Women who use combination hormonal contraceptives should be strongly advised not to smoke.

Ortho Evra – In January 2008, the FDA approved changes to the labeling of the Ortho Evra Contraceptive Transdermal Patch. The revised label reflects new research demonstrating that women who use the patch are at an increased risk of developing serious and, in some cases, life-threatening blood clots in the veins. This condition is called venous thromboembolism (VTE). Patients at higher risk of blood clots should discuss the use of Ortho Evra versus other birth control options with their healthcare providers.]

[INFORMATIONAL NOTE:

• cerebrovascular disease or coronary artery disease
• history of deep vein thrombosis, pulmonary embolism,
• untreated hypertension
• diabetes with vascular complications
• estrogen or progestin dependent neoplasia, including breast or endometrial cancer
• undiagnosed abnormal vaginal bleeding
• known or suspected pregnancy
• active liver disease or liver tumor (benign or malignant)
• age older than 35 years and heavy cigarette smoking (≥15 cigarettes per day).
• kidney or adrenal gland insufficiency
• headaches with focal neurological symptoms or migraine headaches (with or without aura) if > 35 years of age
• thrombogenic valvular or rhythm diseases of the heart
• cholestatic jaundice of pregnancy or with prior hormonal contraceptive use
• major surgery with prolonged immobilization
• thrombophlebitis or thromboembolic disorders, valvular heart disease with complications
• hypercoagulopathies (inherited or acquired), known thrombophilic conditions

Non-Oral Contraceptives are contraindicated in patients with any of the following:
• known or suspected pregnancy or as a diagnostic test for pregnancy (all);
• undiagnosed vaginal bleeding (all);
• known or suspected malignancy of breast (all);
• active thrombophlebitis, or current or past history of thromboembolic disorders, or cerebral vascular disease (all);
• significant liver disease (all);
• acute pelvic inflammatory disease or history of pelvic inflammatory disease (all);
• known or suspected uterine or cervical neoplasia, or unresolved, abnormal Pap smear; genital bleeding of unknown etiology (all);
• acute liver disease or liver tumor (benign or malignant) (all);
• Untreated hypertension (all);
• heavy smoking (≥15 cigarettes per day) and over age 35 (all);
• congenital or acquired uterine anomaly including fibroids if they distort the uterine cavity (Mirena, Liletta, Skyla);
• untreated acute cervicitis or vaginitis, including bacterial vaginosis or other lower genital tract infections until infection is controlled (Mirena, Liletta, Skyla);
• conditions associated with increased susceptibility to pelvic infections (Mirena, Liletta, Skyla);
• a previously inserted IUD that has not been removed (Mirena, Liletta, Skyla);
• postpartum endometritis or infected abortion in the past 3 months (Mirena, Liletta, Skyla);
• diabetes with vascular involvement, headaches with focal neurological symptoms (NuvaRing, Xulane)
• valvular heart disease with thrombogenic complications (NuvaRing, Xulane);
• major surgery with prolonged immobilization (NuvaRing, Xulane);
• carcinoma of the endometrium, breast or other known or suspected estrogen or progestin dependent neoplasia (NuvaRing, Nexplanon, Liletta, Skyla, Mirena);
• cholestatic jaundice of pregnancy or jaundice with prior hormonal contraceptive use (NuvaRing, Xulane)]

Policy:
(NOTE: For Medicare Advantage, please refer to the Medicare Coverage Section below for coverage guidance)

I. Oral and Transdermal Contraceptives

A. Oral and Transdermal contraceptives are considered medically necessary if used for birth control (for contraception) when a member has a benefit plan that provides coverage for female contraceptive.

[INFORMATIONAL NOTE: The following statement represents the interpretation of the New Jersey State Mandate on Prescription Female Contraceptives by Horizon Blue Cross Blue Shield of New Jersey (Horizon BCBSNJ) which must be strictly observed when handling pre-authorizations, claims, inquiries, and other matters pertaining to prescription female contraceptives.

When a member has a benefit plan which provides prescription coverage, the law requires coverage for expenses incurred in the purchase of prescription female contraceptives.

Please note that self-insured accounts are exempt from this mandate. However, they have the option to adopt the law upon renewal of the contract. In addition, certain religious employers may request an exclusion from this mandate if the coverage conflicts with the religious employer's bona fide religious beliefs and practices.]

B. Oral and Transdermal contraceptive are considered medically necessary if used for the following FDA approved indications other than birth control (for other than contraception)
1. Acne vulgaris
2. Premenstrual dysphoric disorder (PMDD)
3. Raise folate levels
4. Menopause - Moderate to severe abnormal vasomotor function
5. Prophylaxis treatment in postmenopausal osteoporosis, in women with an intact uterus;
C. Oral and Transdermal contraceptive are considered medically necessary if used for the following off-label indications:
1. Amenorrhea
2. Dysfunctional uterine bleeding
3. Endometriosis
4. Hirsutism
5. Polycystic ovary syndrome

D. All other uses of oral and transdermal contraceptives are considered investigational.

A. Non-Oral Non-Transdermal Contraceptives are considered medically necessary if used for birth control (for contraception) when a member has a benefit plan that provides coverage for female contraceptive.
B. Non-Oral Non-Transdermal Contraceptives are considered medically necessary if used for the following FDA approved indications:
1. endometriosis-associated pain
2. heavy menstrual bleeding

C. Non-Oral Non-Transdermal Contraceptives are considered medically necessary if used for the following off-label indications
1. adjunctive and/or palliative therapy for advanced (recurrent or metastatic) hormone dependent endometrial carcinoma
2. adjunctive and/or palliative therapy for advanced (recurrent or metastatic) renal carcinoma
3. central and peripheral forms of precocious puberty who are intolerant to GnRH analog therapy
4. adjunctive and/or palliative therapy for advanced (recurrent or metastatic) hormone dependent breast carcinoma
5. dysfunctional uterine bleeding
6. endometriosis
7. endometrial hyperplasia, prophylaxis
8. endometrial hyperplasia
9. postmenopausal symptoms (including hot flashes)
10. hirsutism
11. homozygous sickle cell disease
12. obesity hypoventilation syndrome
13. obstructive sleep apnea syndrome and hypersomnolence in adults
14. polycystic ovary syndrome
15. paraphilia in men (including voyeurism, exhibitionism, erotic sadism, transvestism, and pedophilia)
D. All other uses not listed above for non-oral hormonal contraceptives are considered investigational.

E. The use of subcutaneously implanted estrogen pellets for hormone replacement therapy in women is considered investigational.

[INFORMATIONAL NOTE: There are no FDA approved formulations of these pellets available in the US. The NDA for Estrapel, Bartor Pharmacal’s estrogen pellet product, was first presented to the FDA advisory committee in 1978. The committee requested more information such as estradiol serum levels and endometrial hyperplasia effects. The NDA was presented to the committee again in 1980. Nonetheless, the committee concluded that the study lacked the data to be able to evaluate Estrapel’s efficacy. Bartor then conducted another randomized, placebo-controlled trial that was submitted to the FDA in 1983 and again in 1986. The committee determined that the study was not acceptable. However, the FDA did allow estrogen pellets to be used under compassionate INDs after the committee met in 1980. In 1988, the committee ultimately recommended the discontinuation of compassionate INDs for estrogen pellets due to the lack of sound scientific data regarding their safety and efficacy.]

There is no National Coverage Determination (NCD). In the absence of an NCD, coverage decisions are left to the discretion of Local Medicare Carriers. Novitas Solutions, Inc, the Local Medicare Carrier for jurisdiction JL, has not issued a determination for this service. Therefore, Medicare Advantage Products will follow the Horizon Policy.

Medicaid Coverage

For Horizon NJ Health members, please follow this link for the corresponding HNJH drug policy https://services3.horizon-bcbsnj.com/ddn/NJhealthWeb.nsf

________________________________________________________________________________________

Horizon BCBSNJ Medical Policy Development Process:

This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

___________________________________________________________________________________________________________________________

Index:
Female Hormones (Non-Oral Hormonal Contraceptives, Oral Contraceptives, Implantable Estrogens)
Non-Oral Hormonal Contraceptives
Contraceptives, Non-Oral Hormonal
Oral Contraceptives
Contraceptives, Oral
Implantable Estrogens
Depo-Provera
Depo-SubQ Provera 104
Levonorgestrel Implant System
Lunelle
Implant System, Levonorgestrel
Medroxyprogesterone Injection
Mirena
Norplant
NuvaRing
Ortho Evra
Transdermal Contraceptive Patch
Estrogen Pellets as Hormone Replacement Therapy for Menopausal Women
Hormone Replacement Therapy
Implantable Estrogen
Estrogen, Implantable
Long-acting reversible contraceptives
LARC

References:

1. 2004 Physicians' Desk Reference. 58th Edition. Medical Economics Publishing Company.

2. FDA Talk Paper. Update on Advisory for Norplant Contraceptive Kits. July 26, 2002. http://www.fda.gov/bbs/topics/ANSWERS/2002/ANS01161.html (accessed 8/13/2003)

3. Information on Mirena from the FDA website. http://www.fda.gov and from Berlex Laboratories website. http://www.berlex.com (accessed 10/03/01).

4. Information on Lunelle from the FDA website. http://www.fda.gov (accessed 10/03/01).

5. ECRI Hotline Response: Levonorgestrel Intrauterine System (Mirena) for contraception, menorrhagia, and hormone replacement therapy. Sept. 14, 2001.

6. Information on NuvaRing from the FDA website http://www.fda.gov (accessed 10/08/01).

7. U.S. Food and Drug Administration. FDA Talk Paper: FDA Approves First Hormonal Contraceptive Skin Patch. November 20, 2001.http://www.fda.gov/bbs/topics/ANSWERS/2001/ANS01119.html (accessed 12/20/2001).

8. Ortho Evra - A contraceptive patch. The Medical Letter. January 21, 2002;44(W1122C):8-9.

9. A progestin-releasing intrauterine device for long-term contraception (Mirena). The Medical Letter. January 22, 2001;43(1096):7-8.

10. McEvoy GK, eds., American Formulary Service. Bethesda, MD: American Society of Health System Pharmacists. 2004.

11. Depo-SubQ Provera 104 prescribing information. Pharmacia and Upjohn Co. New York, NY; 2005 March.

12. Implanon prescribing information. Merck & Co. Whitehouse Station, NJ. February 2012.

13. United States Pharmacopeia Drug Information, 2006.

14. NJ State mandate entitled Prescription Female Contraceptives. Effective date: 07/03/06. Applicable citations: N.J.S.A. 17:48E-35.29 (Health Service Corp), N.J.S.A 26:2J-4.30 (HMO), N.J.S.A 52:14-17.29j (SHBP), N.J.S.A 17B:27A-7.12 (Individual), and N.J.S.A 17B:27A-19.15 (Small Employer).

15. Ortho Evra® package insert. Janssen Pharmaceuticals. Titusville, NJ; December 2013

16. Nuvaring® package insert. Merck & Co. Whitehouse Station, NJ; December 2013

17. Depo-Provera® package insert. Pharmacia & Upjohn Company. New York, NY; April 2012

18. Micromedex® Healthcare Series, (electronic version). Thomson Micromedex, Greenwood Village, Colorado, USA. Available at: http://www.thomsonhc.com (cited: 01/13/2014).

19. Mirena® package Insert. Bayer Healthcare Pharmaceuticals. Wayne, NJ; February 2013

20. Henshaw R, Colye C, et al. A retrospective cohort study comparing microwave endometrial ablation with levonorgestrel-releasing intrauterine device in the management of heavy menstrual bleeding. Australian and New Zealand Journal of Obstetrics and Gynecology 2002;42:(2):205-209.

21. FDA News. FDA approves update to label on birth control patch. January 2008. http://www.fda.gov/bbs/topics/NEWS/2008/NEW01781.html (accessed 9/3/08).

22. Gupta B, Mittal R, et al. Levonorgestrel-releasing intrauterine system vs. transcervical endometrial resection for dysfunctional uterine bleeding. International Journal of Gynecology and Obstetrics July 2006:95:261-266.

23. Hurskainen R, Teperi, J, et al. Quality of life and cost-effectiveness of levonorgestrel-releasing intrauterine system versus hysterectomy for treatment of menorrhagia: a randomised trial. The Lancet January 2001;357:273-277.

24. Milsom I, et al. The levonorgestrel-releasing intrauterine system as an alternative to hysterectomy in peri-menopausal women. Contraception 2007;S152-S154.

25. Monteiro I, Diaz, J, Bahamondes, L, et al. Therapeutic use of levonorgestrel-releasing intrauterine system in women with menorrhagia. Contraception 2002 May;65(5):325-328.

26. Crosignani P, Vercellini, P, et al. Levonorgestrel-releasing intrauterine device versus hysteroscopic endometrial resection in the treatment of dysfunctional uterine bleeding. Obstet Gynecol 1997 Aug;90(2):257-63.

27. Clinical Pharmacology - A Gold Standard Product. Available at: http://clinicalpharmacology.com/default.asp?failcode=userlogout [January 2014].

28. FDA News. FDA approves Additional Use for IUD Mirena to treat heavy menstrual bleeding in IUD users. October 1, 2009. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm184747.htm (accessed 10/9/09).

29. U.S. Medical Eligibility Criteria for Contraceptive Use, 2010: adapted from the World Health Organization Medical Eligibility Criteria for Contraceptive Use, 4^th Edition. MMWR 2010; 59 (RR04);1-6.

30. MICROMEDEX® 1.0 (Healthcare Series). DRUGDEX® Evaluations. Available at: http://www.thomsonhc.com. Accessed January 2014

31. Goodman NF, Cobin RH, Ginzburg SB, et al. AACE Medical Guidelines for Clinical Practice for the Diagnosis and Treatment of Menopause. Endocr Pract. 2011;17(Suppl 6)