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; the 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-1 and ELARIS EM-2 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 unknown. 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

Percent Change from Baseline in Lumbar Spine BMD at Month 61



EM-1

ORILISSA
150 mg QD
Once Daily

ORILISSA
200 mg BID
Twice Daily

Placebo

N 183 180 277
Percent Change from Baseline, %
-0.3 -2.6 0.5
Treatment Difference, % (95% CI)

-0.9

(-1.3, -0.4)

-3.1

(-3.6, -2.6)

 


EM-2

ORILISSA
150 mg QD
Once Daily

ORILISSA
200 mg BID
Twice Daily

Placebo

N 174 183 271
Percent Change from Baseline, %
-0.7 -2.5 0.6
Treatment Difference, % (95% CI)

-1.3

(-1.8, -0.8)

-3.0

(-3.5, -2.6)

 
  • The effect of ORILISSA on BMD was assessed by dual-energy X-ray absorptiometry (DXA)
  • In Studies EM-1 and EM-2, there was a dose-dependent decrease in BMD in ORILISSA-treated subjects compared to an increase in placebo-treated subjects
  • In the blinded extension Studies EM-3 and EM-4, continued bone loss was observed with 12 months of continuous treatment with ORILISSA

Dose-dependent Changes in BMD1

Percent Change from Baseline in Lumbar Spine BMD in Subjects Who Received 12 Months of ORILISSA and had Follow-up BMD 6 Months off Therapy in Studies EM-2/EM-4

dose-dependent changes in BMD graph

Percent Change from Baseline in Lumbar Spine BMD in Subjects Who Received 12 Months of ORILISSA and had Follow-up BMD 12 Months off Therapy in Studies EM-2/EM-4

dose-dependent changes in BMD graph

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

Mean Bleeding/Spotting Days and Mean Intensity Scores at Month 3

Mean Bleeding/Spotting Days and Mean Intensity Scores at Month 3

Intensity for subjects who reported at least 1 day of bleeding or spotting during 28 day interval.
Scale ranges from 1 to 4: 1=spotting, 2=light, 3=medium, 4=heavy
Subjects classified their flow of menstrual bleeding (if present in the last 24 hours) using an electronic daily diary.

  • ORILISSA also demonstrated a dose-dependent increase in the percentage of women with amenorrhea (defined as no bleeding or spotting in a 56-day interval) over the treatment period

  • 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) to 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


  • ORILISSA is contraindicated in women with concomitant use of strong organic anion transporting polypeptide (OATP) 1B1 inhibitors (e.g., cyclosporine and gemfibrozil)1

Established Drug Interactions Based on Drug Interaction Trials1

Concomitant Drug Class:
Drug Name
Effect on Concentration of ORILISSA or Concomitant Drug Clinical Recommendations
Antiarrhythmics: digoxin ↑ digoxin Clinical monitoring is recommended for digoxin when co-administered with ORILISSA.
Antimycobacterial: rifampin ↑ elagolix Concomitant 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 ↓ midazolam Consider increasing the dose of midazolam and individualize therapy based on patient’s response.
Statins: rosuvastatin ↓ rosuvastatin Consider increasing the dose of rosuvastatin.

The direction of the arrow indicates the direction of the change in the area under the curve (AUC)


↑  =  increase
↓  =  decrease


This is not all of the information you need to know about Drug Interactions with ORILISSA. For more information, please see Section 7 DRUG INTERACTIONS in the Orilissa full Prescribing Information


For more information on drug-drug interaction see clinical pharmacology, tables 10 and 11 in ORILISSA Full Prescribing Information


Drugs with no observed clinically significant changes in ORILISSA exposures¹

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).