Effective Date

Date of Origin 

01-01-2025            

01-01-2024

VEOZAH®

(fezolinetant)

Tablet

Treatment of moderate to severe vasomotor symptoms due to menopause

1

Vasomotor Symptoms

Menopause is the final stage of ovarian physiology and signifies the time when reproductive function is lost due to complete depletion of finite ovarian follicle supply.(2) It is defined as 12 months of amenorrhea and occurs at an average age of 51.3 years in the United States.(3) The process of menopause is directly related to ovarian aging, all aspects of the hypothalamic-pituitary-ovarian-uterine axis are altered with time. Estrogen withdrawal during the menopause transition (MT) is associated with alterations in the hypothalamic thermoregulatory neutral zone, a group of neurons that regulate body temperature.(2) This group of neurons, known as KNDy neurons for the co-expression of kisspeptin, neurokinin B (NKB), and dynorphin, are normally inhibited by estrogen are instead overstimulated during the MT and can cause dysregulation of body temperature. These changes lead to an increased frequency of bodily reaction to internal and environmental triggers that prevent heat loss. Vasomotor symptoms (VMS), also known as hot flashes, are known as the hallmark manifestations of the MT which include feelings of flushing, warmth sensation, skin reddening, and perspiration.(3) 

Symptoms of menopause are most common and severe in the first 1 to 2 years after the final menstrual period (FMP) and can continue for more than a decade for some patients.(2) VMS affect as many as 80% of midlife patients.(3) Moderate to severe VMS is defined as 7 or more episodes per day or 50-60 episodes per week.(1) Data show that patients who experience frequent VMS (greater than 6 days in the previous 2 weeks) experience higher rates of anxiety, depression, difficulty sleeping and overall impaired quality of life.(4) Frequent VMS persisted on average 7.4 years and appear to be linked to cardiovascular, bone, and cognitive risks.(6) 

Hormone therapy (HT) remains the gold standard for relief of VMS and has been shown to prevent bone loss and fracture.(6) Patients with significant sleep or mood disturbance during the MT may also benefit from HT. HT reduces symptom frequency by 90% as quickly as one month after initiation.(3) In the Women's Health Initiative (WHI), patients with VMS experienced an 85% reduction in symptoms after treatment with estrogen plus progesterone.(2) Patients 60 years of age or younger who are within 10 years of menopause onset and have no contraindications, the benefit-risk ratio is supportive for HT of bothersome VMS.(6) HT is considered safe and effective in low-risk patients without underlying coronary heart disease or history of breast cancer.(2) The most common acute adverse effects of HT includes breast pain and uterine bleeding. HT has shown improvement in glycemic control and insulin resistance in patients with and without type 2 diabetes, as well as other cardiovascular disease risk factors.(3) For patients more than 10 years from the onset of menopause or 60 years or older who initiate HT, the benefit-risk ratio appears to be less favorable due to the greater absolute risks of coronary heart disease (CHD), stroke, venous thromboembolism (VTE), and dementia.(6) 

Estrogen regimens are available as estrogen-only, combined with progestin, or combined with a serum estrogen receptor modulator (SERM).(2) Systemic estrogens can be prescribed as oral drugs; transdermal patches, sprays and gels; or as vaginal rings. Meta-analysis of estrogen preparations found no evidence of a significant difference between transdermal and oral preparations for alleviating VMS. Estrogen-alone therapy (ET) can be used for symptomatic patients without a uterus and estrogen plus progesterone therapy (EPT) or tissue-selective estrogen complex (TSEC) for patients with a uterus to protect against endometrial neoplasia.(6) Vaginal formulations do not require progestin as these have not been shown to induce endometrial proliferation.(2)

Nonhormone options are important considerations for patients who are not candidates for HT. Paroxetine 7.5 mg was the first nonhormonal drug FDA approved for the treatment of moderate to severe VMS, with improvements found in VMS severity and frequency for up to 24 months, along with improvements in sleep disruption, without weight gain or negative effects on libido. Other nonhormone medications that are recommended to reduce VMS include selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), gabapentin, and oxybutynin. Paroxetine, escitalopram, citalopram, venlafaxine, and desvenlafaxine and have been shown to significantly reduce VMS in large, double-blind, randomized, controlled trials (RCTs) of symptomatic patients. Sertraline and fluoxetine trend towards improvement but were statistically insignificant and are not recommended. Duloxetine has been shown to reduce VMS in smaller studies. Hot flash reductions vary from 25% to 69% with these treatments, with improvement in hot flash severity and frequency from 27% to 61%. A pooled analysis from three RCTs showed that 10 mg to 20 mg of escitalopram, 0.5 mg of oral 17-beta-estradiol, and 75 mg of venlafaxine daily resulted in comparable reductions of VMS frequency. Gabapentin, an antiepileptic, has shown that it has improved the frequency and severity of VMS in several trials studying the dose of 900 mg/day. Gabapentin at higher doses (titrated to 2,400 mg/d) has been shown to be as beneficial as estrogen (conjugated equine estrogens 0.625 mg/d) in reducing hot flash scores. Oxybutynin, an antimuscarinic, demonstrated in one prospective study and two randomized double-blind studies, that doses ranging from 2.5 mg or 5 mg twice daily up to 15 mg extended-release daily, significantly improved moderate to severe VMS.(7)

Efficacy

The efficacy of VEOZAH for the treatment of moderate to severe VMS due to menopause was evaluated in the first 12-week, randomized, placebo-controlled, double-blind portion of each of the two phase 3 clinical trials. Patients on placebo at 12-weeks were re-randomized to VEOZAH for a 40-week extension to evaluate safety for up to 52 weeks. A total of 522 patients in Trial 1 (NCT04003155) and 500 patients in Trial 2 (NCT04003142) who had a minimum average of 7 moderate to severe VMS per day were randomized to one of two doses of fezolinetant or placebo. The co-primary efficacy endpoints for both trials were the mean change from baseline in moderate to severe VMS frequency and severity to Weeks 4 and 12. Data from each trial showed statistically significant reduction from baseline in the frequency of moderate to severe VMS for VEOZAH 45 mg compared to placebo at Weeks 4 and 12. Both trials also demonstrated a statistically significant reduction from baseline in the severity of moderate to VMS at Weeks 4 and 12 for VEOZAH 45 mg compared to placebo.(1)

Safety

VEOZAH is contraindicated in women with any of the following conditions:(1)

• Known cirrhosis
• Severe renal impairment or end-stage renal disease
• Concomitant use with CYP1A2 inhibitors

VEOZAH is a neurokinin 3 (NK3) receptor antagonist that blocked the neurokinin B (NKB) binding on the kisspeptin/neurokinin B/dynorphin (KNDy) neuron to modulate neuronal activity in the thermoregulatory center. Elevations in serum transaminase levels greater than three times the upper limit of normal (ULN) occurred in 2.3% of women receiving VEOZAH. Labeling recommends baseline bloodwork be evaluated for hepatic function and injury prior to VEOZAH initiation. If baseline hepatic transaminase evaluation is less than two times the ULN and the total bilirubin is normal, VEOZAH can be initiated. Follow up evaluations of hepatic transaminase concentrations are recommended at 3, 6, and 9 months after initiation or when symptoms suggest liver injury.(1)

1

VEOZAH prescribing information. Astellas Pharma US LLC. May 2023.

2

Santoro N, et al. The Menopause Transition: Signs, Symptoms, and Management Options. The Journal of Clinical Endocrinology & Metabolism, Jan 2021; 106(1): 1-15. https://doi.org/10.1210/clinem/dgaa764

3

Khan SJ, Kapoor E, Faubion SS, Kling JM. Vasomotor Symptoms During Menopause: A Practical Guide on Current Treatments and Future Perspectives. Int J Womens Health. 2023 Feb 14;15:273-287. doi:10.2147/IJWH.S365808. 

4

Avis NE, Crawford SL, Greendale G, et al. Duration of Menopausal Vasomotor Symptoms Over the Menopause Transition. JAMA Intern Med. 2015;175(4):531–539. doi:10.1001/jamainternmed.2014.8063.

5

Beaudoin FL, et al. Fezolinetant for Moderate to Severe Vasomotor Symptoms Associated with Menopause: Effectiveness and Value; Final Evidence Report. Institute for Clinical and Economic Review, January 23, 2023. https://icer.org/assessment/vasomotor-symptoms-menopause-2022/#overview

6

The 2022 hormone therapy position statement of The North American Menopause Society. (2022). Menopause, 29(7), 767–794. DOI: 10.1097/GME.0000000000002028.

7

The 2023 nonhormone therapy position statement of The North American Menopause Society. (2023). Menopause, 30(6), 573-590. DOI: 10.1097/GME.0000000000002200.

Veozah

fezolinetant tab

45 MG

M ; N ; O ; Y

N

Veozah

fezolinetant tab

45 MG

30

Tablet

30

DAYS

Veozah

fezolinetant tab

45 MG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Veozah

fezolinetant tab

45 MG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Initial Evaluation

Target Agent(s) will be approved when BOTH of the following are met:

1. ONE of the following:
   1. The requested agent is eligible for continuation of therapy AND ONE of the following:  

1. 1. 1. The patient has been treated with the requested agent (starting on samples is not approvable) within the past 90 days OR
      2. The prescriber states the patient has been treated with the requested agent (starting on samples is not approvable) within the past 90 days AND is at risk if therapy is changed OR
   2. The patient has a diagnosis of vasomotor symptoms AND ALL of the following:
      1. The patient is menopausal AND
      2. The patient's symptoms are moderate to severe (i.e., 7 or more episodes per day or 50 or more episodes per week) AND
      3. Baseline (prior to starting the requested agent) hepatic function (i.e., ALT, AST, serum bilirubin [total and direct]) has been evaluated AND 
      4. Hepatic transaminases are less than two times the upper limit of normal (ULN) and the total bilirubin is normal AND 
      5. ONE of the following:
         1. The patient has tried and had an inadequate response to at least ONE menopausal hormone therapy (i.e., estrogen therapy [ET] or estrogen plus progesterone therapy [EPT] including oral, transdermal patches, sprays and gels, and vaginal ring agents) OR 
         2. The patient has an intolerance or hypersensitivity to at least ONE menopausal hormone therapy OR
         3. The patient has an FDA labeled contraindication to ALL menopausal hormone therapies OR
         4. The patient is over 60 years of age or onset of menopause was greater than or equal to 10 years prior AND
      6. ONE of the following:
         1. The patient has tried and had an inadequate response to at least ONE nonhormonal therapy used to treat vasomotor symptoms of menopause (i.e., paroxetine, escitalopram, citalopram, venlafaxine, desvenlafaxine, duloxetine, gabapentin, oxybutynin) OR 
         2. The patient has an intolerance or hypersensitivity to at least ONE nonhormonal therapy used to treat vasomotor symptoms of menopause OR
         3. The patient has an FDA labeled contraindication to ALL nonhormonal therapies used to treat vasomotor symptoms of menopause OR
   3. The patient has another FDA labeled indication for the requested agent and route of administration AND
2. The patient does NOT have any FDA labeled contraindications to the requested agent 

Length of Approval: 3 months

NOTE: If Quantity Limit applies, please refer to Quantity Limit Criteria. 

Renewal Evaluation 

Target Agent(s) will be approved when ALL of the following are met:

1. The patient has been previously approved for the requested agent through the plan’s Prior Authorization process [Note: patients not previously approved for the requested agent will require initial evaluation review] AND
2. The patient has had clinical benefit with the requested agent AND
3. BOTH of the following:
   1. Hepatic function (i.e., ALT, AST, serum bilirubin [total and direct]) has been evaluated since starting the requested agent AND 
   2. Hepatic transaminases are less than two times the upper limit of normal (ULN) and the total bilirubin is normal AND
4. The patient does NOT have any FDA labeled contraindications to the requested agent 

Length of Approval: 12 months 

NOTE: If Quantity Limit applies, please refer to Quantity Limit Criteria. 

Quantity limit for the Target Agent(s) will be approved when ONE of the following is met: 

1. The requested quantity (dose) does NOT exceed the program quantity limit OR
2. The requested quantity (dose) exceeds the program quantity limit AND ONE of the following:
   1. BOTH of the following:
      1. The requested agent does NOT have a maximum FDA labeled dose for the requested indication AND
      2. There is support for therapy with a higher dose for the requested indication OR
   2. BOTH of the following:
      1. The requested quantity (dose) does NOT exceed the maximum FDA labeled dose for the requested indication AND
      2. There is support for why the requested quantity (dose) cannot be achieved with a lower quantity of a higher strength that does NOT exceed the program quantity limit OR
   3. BOTH of the following:
      1. The requested quantity (dose) exceeds the maximum FDA labeled dose for the requested indication AND
      2. There is support for therapy with a higher dose for the requested indication

Length of Approval: up to 12 months