Appeal type: Formulary Exception
Decision: Upheld

Diagnosis: Menopause.
Treatment: Prempro 0.3-1.5mg (milligram) Tablet, pre-service.

The insurer denied the Prempro 0.3-1.5mg (milligram) Tablet, pre-service.  The denial is upheld.

The patient is a female with menopausal symptoms.  She has tried and failed numerous options.  She was placed on Prempro with improvement in symptoms.  The request is to continue.  

The requested Prempro was denied because the patient has not tried and failed the formulary options.  This is being appealed.

No, the health plan should not cover the proposed treatment with Prempro.

According to the American College of Obstetrics and Gynecology, studies of the efficacy of hormone therapy (HT) for the treatment of vasomotor symptoms have principally investigated standard doses of hormone therapy. Although hormone therapy is well tolerated by most women, standard doses may cause adverse effects, such as breast tenderness, vaginal bleeding, bloating, and headaches. Low-dose and ultra-low systemic doses of estrogen may be associated with a better adverse effect profile than standard doses and may reduce vasomotor symptoms in some women.  Examples of low-dose systemic estrogen therapy formulations include 0.30.45 milligrams per day (mg/d) of oral conjugated equine estrogen, 0.5 milligrams per day (mg/d) of oral micronized estradiol, 5.0 micrograms per day of ethinyl estradiol, and 0.0250.0375 milligrams per week of transdermal estradiol (patch). There also are low-dose formulations of estradiol available in topical gels, creams, and sprays that are approved by the United States Food and Drug Administration (FDA). There is good evidence that oral and transdermal low-dose estrogen regimens effectively alleviate vasomotor symptoms in women. The Heart Outcomes Prevention Evaluation, a large trial that assessed the efficacy of different doses of hormone therapy on vasomotor symptoms in more than 2,500 postmenopausal women, found a similar reduction in vasomotor symptoms with a conjugated equine estrogen dosage of 0.625 milligrams per day and all lower combination doses. Another study of 333 women randomized to receive various doses of estradiol or placebo found that a dosage as low as 0.5 milligrams per day of oral estradiol is effective in treating hot flushes.

The results of studies that assessed the efficacy of ultra-low doses of estrogen (0.25 milligrams of oral micronized estradiol and 0.014 milligrams of transdermal estradiol) to treat vasomotor symptoms have been mixed, and currently these doses are not Food and Drug Administration (FDA) approved for this indication. Some studies have shown improvement in vasomotor symptoms with ultra-low dose estrogen alone or in combination with progestin. For example, a randomized controlled trial (RCT) of 425 women demonstrated that 41% of women experienced a reduction in moderate and severe hot flushes with ultra-low dose estradiol therapy (0.014 milligrams per day estradiol patch) compared with placebo. However, other studies have not shown a benefit for the treatment of vasomotor symptoms. In a randomized controlled trial (RCT) of 333 women, a 0.25-milligram dose of oral estradiol was not more effective than placebo in treating hot flushes.

The degree of improvement of vasomotor symptoms from low-dose and ultra-low dose preparations has not been as extensively studied as with standard-dose preparations. Although women will experience improvement in symptoms with low and ultra-low doses of hormone therapy, lower doses may not be as effective as traditional doses of hormone therapy in alleviating vasomotor symptoms. Nonetheless, given the variable response to hormone therapy and the associated risks, it is recommended that health care providers individualize care and treat women with the lowest effective dose for the shortest duration that is needed to relieve vasomotor symptoms.

The risks of systemic combined hormone therapy include thromboembolic disease and breast cancer. The majority of trials that analyzed the safety of hormone therapy have assessed preparations containing conjugated equine estrogen alone or in combination with medroxyprogesterone acetate. The Women's Health Initiative (WHI) study, a large randomized controlled trial (RCT) of healthy menopausal women aged 50-77 years, demonstrated a slightly increased risk of breast cancer, coronary heart disease, stroke, and venous thromboembolic events and a decreased risk of fractures and colon cancer after an average of five years of combined hormone therapy. Among women receiving estrogen only, there was an increased risk of thromboembolic events, but not an increased risk of cardiovascular events or breast cancer. It is difficult to generalize these findings to younger women who are recently menopausal because the Women's Health Initiative (WHI) was aimed at assessing hormone therapy for primary coronary heart disease prevention in women, many of whom were past the menopausal transition.

A reanalysis of the Women's Health Initiative (WHI) results in women younger than 60 years and within ten years of menopause has suggested a possible cardioprotective effect of hormone therapy for women in this group. However, a follow-up study of the Women's Health Initiative (WHI) with 13 years of cumulative follow-up data confirmed that the risk of conjugated equine estrogen and medroxyprogesterone acetate outweighed the benefits. Similarly, a Cochrane review of hormone therapy that included 23 studies and more than 42,000 participants concluded that hormone therapy should not be used for primary or secondary disease prevention because the risks of use outweigh the benefits.

The use of alternative forms of estrogen and progestin may be associated with a different risk profile. For example, observational studies suggest that transdermal estrogen may have a lower risk of venous thromboembolism compared with oral regimens. Additional data from randomized controlled trials (RCTs) are needed to compare the safety and efficacy of various regimens.

In review of the medical record and current literature there is not one form or dose of hormone therapy that is superior to others. The goal of treatment is to individualize care and to treat with the lowest effective dose for the shortest duration that is needed to relieve symptoms.  Given the record indicates that the patient has tried and failed multiple other options but has had relief with Prempro, this would be a necessary option.  However looking at the formulary options, the option of Premarin tablet with a medroxyprogesterone tablet is equivalent to the Prempro whereas the other options of Climara pro, Jinteli, and Mimvey are not.  The Premarin and medroxyprogesterone are the same medications as in Prempro so should be as effective as the non-formulary drug.  Since the patient has tolerated Prempro there should be no indication that this would cause adverse effects.  Therefore because there is a formulary equivalent, the health plan should not cover the proposed treatment unless the formulary option is tried and failed.