Appeal type: Formulary Exception
Decision: Overturned

Diagnosis: Pelvic pain
Issue under review: Formulary exception for Orilissa

Determination:
The health plan should cover the Formulary exception for Orilissa.

The patient is an adult female with endometriosis-associated pelvic pain.  She has tried several oral contraceptives and has had surgery with removal of implants without relief.  She was started on Orilissa and has had relief of symptoms.

GnRH antagonists suppress pituitary gonadotropin hormone production and create a hypoestrogenic state. Unlike GnRH agonists, these agents are effective immediately, do not cause an initial surge in luteinizing hormone and follicle stimulating hormone, and do not require seven to 14 days for GnRH suppression. They are available in both oral and injectable forms. The GnRH antagonist induces a dose-dependent hypoestrogenic state to inhibit endometriotic cell proliferation. Symptom relief and adverse events such as vasomotor phenomena, vaginal atrophy, and bone loss are also dose-dependent. GnRH antagonists provide a treatment option for women who do not respond to NSAIDs, estrogen-progestin contraceptives, or progestins, and they are easier to dose than GnRH agonists.

In two phase-three trials, women in both elagolix groups reported significantly reduced symptoms at three months of treatment. In both trials, at three months, meaningful reductions in dysmenorrhea pain were reported by about 44 percent of the low-dose elagolix group, 74 percent of the high-dose elagolix group, and 21 percent of the placebo group. Nonmenstrual pelvic pain was decreased in 50, 56, and 36 percent of women in the low-dose, high-dose, and placebo groups, respectively. At six months, these responses persisted compared with placebo. Also at six months, mean changes from baseline in lumbar spine bone density were about -0.5, -2.6, and +0.5 percent in the low-dose, high-dose, and placebo groups, respectively. The improvement in dysmenorrhea in the low-dose elagolix group is modest compared with the approved GnRH agonist, depot-leuprolide acetate. While 72 percent or more of women in all three groups noted an adverse event, the side effect-driven discontinuation rates were 10 percent in both treatment and placebo groups. Women in the treatment groups reported significantly more hot flushes, headache, and insomnia and had higher serum lipids levels compared with women receiving placebo. 

A followup study that extended both treatment groups for an additional six months reported sustained improvements in dysmenorrhea, non-menstrual pelvic pain, and dyspareunia at both doses.

In the US, elagolix is an oral tablet approved for treatment of moderate-to-severe endometriosis-related pain. Similar to GnRH agonists, it can cause hot flushes or night sweats. It is available in doses of 150 mg or 200 mg. While the lowest dose that controls symptoms is preferred, the higher dose may be required for women with dyspareunia as part of their symptomatology. 

In review of the literature the use of Orilissa is a treatment option for women who do not respond to hormonal formulations or anti-inflammatories.  This criterion is met by the patient.  The medication also had fewer side effects and is easier to dose than GnRH agonists.  It is approved for moderate to severe endometriosis related pain.  Both Lupaneta and Synarel are GnRH agonists with a harsh side effect profile.  Lupaneta is an injection that is not easily reversible.  Danazol is not first line medication due to the side effects including weight gain, muscle cramps, decreased breast size, acne, hirsutism, oily skin, decreased high density lipoprotein levels, increased liver enzymes, hot flashes, mood changes, and depression. There are not any formulary equivalents that are GnRH antagonists.  Therefore, in review of the medical literature, the patient meets the literature-based recommendations for the use of Orilissa.  Changing this medication may worsen her medical condition.