Safety and tolerability profile

Safety evaluation from 2 clinical trials where 952 women were treated with ORILISSA1


Serious Adverse Events

Overall, the most common serious adverse events reported for subjects treated with ORILISSA in the two placebo-controlled clinical trials (Studies EM-1 and EM-2) included appendicitis (0.3%), abdominal pain (0.2%), and back pain (0.2%). In these trials, 0.2% of subjects treated with ORILISSA 150 mg once daily and 0.2% of subjects treated with ORILISSA 200 mg twice daily discontinued therapy due to serious adverse reactions compared to 0.5% of those given placebo.


In the extension studies (EM-3 and EM-4, most commonly reported adverse reactions were similar to that noted in placebo-controlled studies (EM-1 and EM-2).1

Discontinuations for both dosage forms were most commonly due to hot flush or night sweats and nausea.


  • Discontinuation rates were 1.1% and 2.5% for patients taking 150 mg QD and 200 mg BID, respectively; majority (59%) occurred within the first 2 months of therapy

  • Associated with discontinuation rates of 0.8% and 1.5% for patients taking 150 mg QD and 200 mg BID, respectively
  • Discontinuations due to nausea (64%) mainly occurred within the first 2 months of therapy

Percentage of patients in ELARIS EM-I and ELARIS EM-II with treatment-emergent adverse reactions occurring in at least 5% of patients (either ORILISSA dosage group) and at a greater incidence than placebo




Symptom
150 mg QD
(N=475)
200 mg BID
(N=477)
Placebo
(N=734)
Hot Flush or Night Sweats24%46%9%
Headache17%20%12%
Nausea11%16%13%
Insomnia6%9%3%
Mood altered, mood swings6%5%3%
Amenorrhea4%7%<1%
Depressed mood, depression, depressive symptoms and/or tearfulness3%6%2%
Anxiety3%5%3%
Arthralgia3%5%3%


ORILISSA leads to a reduction in serum estradiol levels that causes a dose-dependent decrease in bone mineral density (BMD)

  • BMD loss is greater with increasing duration of use and BMD loss may not be completely reversible after stopping treatment1
  • The impact of ORILISSA-associated decreases in BMD on long-term bone health and future fracture risk is unknown1
  • Consider assessment of BMD in patients with a history of low-trauma fracture or other risk factors for osteoporosis or bone loss and do not use in women with known osteoporosis1
  • Limit the duration of use to reduce the extent of bone loss1
  • In Study EM-1, compared to placebo, the mean change from baseline in lumbar spine BMD at 6 months was -0.9% (95% CI: -1.3, -0.4) with ORILISSA 150 mg once daily and -3.1% (95% CI: -3.6, -2.6) with ORILISSA 200 mg twice daily
  • In Study EM-2, compared to placebo, the mean change from baseline in lumbar spine BMD at 6 months was -1.3% (95% CI: -1.8, -0.8) with ORILISSA 150 mg once daily and -3.0% (95% CI: -3.5, -2.6) with ORILISSA 200 mg twice daily
  • In the blinded extension Studies EM-3 and EM-4, continued bone loss was observed with 12 months of continuous treatment with ORILISSA

  • In the blinded extension studies EM-3 and EM-4, patients who received continuous treatment with ORILISSA for 12 months, continuous bone loss was observed
  • The change in lumbar spine BMD over time was analyzed for subjects who received continuous treatment with ORILISSA 150 mg once daily or ORILISSA 200 mg twice daily for up to 12 months and who were then followed after cessation of therapy for an additional 6 months. Partial recovery of BMD was seen in these subjects
  • Consider assessment of BMD in patients with a history of low-trauma fracture or other risk factors for osteoporosis or bone loss


Additional serious safety considerations



  • Women who take ORILISSA may experience a reduction in the amount, intensity or duration of menstrual bleeding, which may reduce the ability to recognize the occurrence of a pregnancy in a timely manner
  • Perform pregnancy testing if pregnancy is suspected, and discontinue ORILISSA if pregnancy is confirmed

  • Suicidal ideation and behavior, including one completed suicide, occurred in subjects treated with ORILISSA in the endometriosis clinical trials
  • ORILISSA users had a higher incidence of depression and mood changes compared to placebo and ORILISSA users with a history of suicidality or depression had an increased incidence of depression
  • Promptly evaluate patients with depressive symptoms to determine whether the risks of continued therapy outweigh the benefits
  • Patients with new or worsening depression, anxiety or other mood changes should be referred to a mental health professional, as appropriate
  • Advise patients to seek immediate medical attention for suicidal ideation and behavior
  • Reevaluate the benefits and risks of continuing ORILISSA if such events occur

  • In clinical trials, dose-dependent asymptomatic elevations of serum alanine aminotransferase (ALT) at least 3-times the upper limit of the reference range occurred during treatment with ORILISSA (150 mg once daily – 1/450, 0.2%; 200 mg twice daily – 5/443, 1.1%; placebo - 1/696, 0.1%). Similar increases were seen in the extension trials (Studies EM-3 and EM-4)
  • Use the lowest effective dose and instruct patients to promptly seek medical attention in case of symptoms or signs that may reflect liver injury, such as jaundice
  • Promptly evaluate patients with observed elevations in liver tests to determine whether the benefits of continued therapy outweigh the risks

  • Based on the mechanism of action of ORILISSA, estrogen-containing contraceptives are expected to reduce the efficacy of ORILISSA. The effect of progestin-only contraceptives on the efficacy of ORILISSA is unknown
  • Advise patients to use of non-hormonal contraceptives during treatment with ORILISSA and for one week after discontinuing ORILISSA

Drug interactions1


The direction of the arrow indicates the direction of the change in AUC


↑  =  increase
↓  =  decrease


Concomitant Drug Class:
Drug Name
Effect on Concentration of ORILISSA or Concomitant DrugClinical Comments
Antiarrhythmics: digoxin↑ digoxinClinical monitoring is recommended for digoxin when co-administered with ORILISSA.
Antimycobacterial: rifampin↑ elagolixConcomitant use of ORILISSA 200 mg twice daily and rifampin is not recommended. Limit concomitant use of ORILISSA 150 mg once daily and rifampin to 6 months.
Benzodiazepines: oral midazolam↓ midazolamConsider increasing the dose of midazolam and individualize therapy based on patient’s response.
Statins: rosuvastatin↓ rosuvastatinConsider increasing the dose of rosuvastatin.

For more information on drug-drug interaction see clinical pharmacology, tables 6 and 7 in ORILISSA Full Prescribing Information


Drugs with no observed clinically significant interactions with ORILISSA¹

No clinically significant changes in ORILISSA exposures were observed when co-administered with rosuvastatin (20 mg once daily), sertraline (25 mg once daily) or fluconazole (200 mg single dose).