Ormeloxifene Side Effects
Ormeloxifene is not included in major clinical practice guidelines (ASCO, NCCN) for any indication, and lacks FDA approval for systemic use, making its side effect profile less well-characterized than established SERMs like tamoxifen and raloxifene. 1
Limited Clinical Data
The absence of ormeloxifene from established guidelines reflects the lack of large-scale randomized controlled trials in Western populations. 1 Unlike raloxifene, which has extensive safety data from trials like MORE, ormeloxifene's adverse event profile comes primarily from smaller studies and international (non-FDA) experience.
Expected SERM Class Effects
Based on the selective estrogen receptor modulator class, ormeloxifene would be anticipated to share common side effects with other SERMs:
Vasomotor Symptoms
- Hot flashes and night sweats are common with all SERMs, including raloxifene and tamoxifen. 2
- Women in early menopause experience these symptoms more frequently. 2
Musculoskeletal Effects
- Leg cramps occur commonly with SERMs, particularly raloxifene, which showed increased leg cramps versus placebo in clinical trials. 2, 3
- Levormeloxifene (a related compound) demonstrated leg cramps in 6% versus 0.8% with placebo. 4
Thromboembolic Risk
- All SERMs, including tamoxifen and raloxifene, increase the risk of venous thromboembolism (VTE). 5
- Deep venous thrombosis and pulmonary embolism are serious adverse effects associated with SERM therapy. 5
- SERMs are contraindicated in women with prior history of DVT or pulmonary embolism. 5
Gynecologic Effects
- Levormeloxifene (structurally related SERM) caused marked increases in leukorrhea (30% vs 3%), increased endometrial thickness (19% vs 1%), and enlarged uterus (17% vs 3%) compared to placebo. 4
- Vaginal discharge occurs more commonly with tamoxifen than aromatase inhibitors. 5
Urogenital Symptoms
- Levormeloxifene showed increased urinary incontinence (17% vs 4%) and increased micturition frequency (9% vs 4%) versus placebo. 4
- Uterovaginal prolapse occurred in 7% versus 2% with placebo. 4
Other Adverse Effects
- Lower abdominal pain (17% vs 6% with placebo for levormeloxifene). 4
- Peripheral edema and influenza-like syndromes are associated with raloxifene. 2
Mechanistic Considerations
Ormeloxifene demonstrates antiestrogenic effects in uterine tissue through modulation of AP-1 mediated pathways and downregulation of IGF-1 expression. 6 This mechanism may theoretically reduce some uterine proliferative effects compared to other SERMs, though clinical confirmation in large trials is lacking.
Critical Clinical Caveat
The lack of inclusion in ASCO 2019 breast cancer risk reduction guidelines (which recommend tamoxifen, raloxifene, exemestane, and anastrozole) and absence from NCCN guidelines indicates insufficient evidence for ormeloxifene's safety and efficacy profile in standard clinical practice. 1 Providers should preferentially use guideline-recommended SERMs with established safety profiles when SERM therapy is indicated. 5