Adverse reactions : תופעות לוואי

7. ADVERSE REACTIONS
The following serious adverse reactions are discussed elsewhere in labeling: • Bone loss [see Warnings and Precautions (6.1)]
• Change in menstrual bleeding pattern and reduced ability to recognize pregnancy [see Warnings and Precautions (6.2)]
• Suicidal ideation, suicidal behavior, and exacerbation of mood disorders [see Warnings and Precautions (6.3)]
• Hepatic transaminase elevations [see Warnings and Precautions (6.4)] 
7.1. Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
The safety of ORILISSA was evaluated in two six-month, randomized, double-blind, placebo- controlled clinical trials [EM-1 (NCT01620528) and EM-2 (NCT01931670)] in which a total of 952 adult women with moderate to severe pain associated with endometriosis were treated with ORILISSA (475 with 150 mg once daily and 477 with 200 mg twice daily) and 734 were treated with placebo. The population age range was 18-49 years old. Women who completed six months of treatment and met eligibility criteria continued treatment in two uncontrolled, blinded six- month extension trials [EM-3 (NCT01760954) and EM-4 (NCT02143713)], for a total treatment duration of up to 12 months.
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.


Adverse Reactions Leading to Study Discontinuation
In the two placebo-controlled clinical trials (Studies EM-1 and EM-2), 5.5% of subjects treated with ORILISSA 150 mg once daily and 9.6% of subjects treated with ORILISSA 200 mg twice daily discontinued therapy due to adverse reactions compared to 6.0% of those given placebo.
Discontinuations were most commonly due to hot flushes or night sweats (1.1% with 150 mg once daily and 2.5% with 200 mg twice daily) and nausea (0.8% with 150 mg once daily and 1.5% with 200 mg twice daily) and were dose-related. The majority of discontinuations due to hot flushes or night sweats (10 of 17, 59%) and nausea (7 of 11, 64%) occurred within the first 2 months of therapy.
In the two extension trials (Studies EM-3 and EM-4), discontinuations were most commonly due to decreased BMD and were dose-related. In these trials, 0.3% of subjects treated with ORILISSA 150 mg once daily and 3.6% of subjects treated with ORILISSA 200 mg twice daily discontinued therapy due to decreased BMD.
Common Adverse Reactions:
Adverse reactions reported in ≥ 5% of women in the two placebo-controlled trials in either ORILISSA dose group and at a greater frequency than placebo are noted in the following table.

Table 2. Percentage of Subjects in Studies EM-1 and EM-2 with Treatment-Emergent Adverse Reactions Occurring in at Least 5% of Subjects (either ORILISSA Dose Group) and at a Greater Incidence than with Placebo
ORILISSA          ORILISSA
Placebo
150 mg Once Daily 200 mg Twice Daily
N=734
N=475             N=477
%                  %             %
Hot Flush                                       24                 46             9 Headache                                        17                 20            12 Nausea                                          11                 16            13 Insomnia                                         6                  9             3 Mood altered, mood swings                        6                  5             3 Amenorrhea                                       4                  7           <1 Depressed mood, depression, depressive
3                    6               2 symptoms and/or tearfulness
Anxiety                                           3                    5               3 Arthralgia                                        3                    5               3 The most commonly reported adverse reactions in the extension trials (EM-3 and EM-4) were similar to those in the placebo-controlled trials.
Less Common Adverse Reactions:
In Study EM-1 and Study EM-2, adverse reactions reported in ≥ 3% and < 5% in either ORILISSA dose group and greater than placebo included: decreased libido, diarrhea, abdominal pain, weight gain, dizziness, constipation and irritability.


Bone Loss
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 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 (Table 3). The percentage of subjects with greater than 8% BMD decrease in lumbar spine, total hip or femoral neck at any time point during the placebo-controlled treatment period was 2% with ORILISSA 150 mg once daily, 7% with ORILISSA 200 mg twice daily and < 1% with placebo. In the blinded extension Study EM-3, continued bone loss was observed with 12 months of continuous treatment with ORILISSA. The percentage of subjects with greater than 8% BMD decrease in lumbar spine, total hip or femoral neck at any time point during the extension treatment period was 8% with continuous ORILISSA 150 mg once daily and 21% with continuous 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 (Table 3). The percentage of subjects with greater than 8% BMD decrease in lumbar spine, total hip or femoral neck at any time point during the placebo-controlled treatment period was < 1% with ORILISSA 150 mg once daily, 6% with ORILISSA 200 mg twice daily and 0% with placebo. In the blinded extension Study EM-4, continued bone loss was observed with 12 months of continuous treatment with ORILISSA. The percentage of subjects with greater than 8% BMD decrease in lumbar spine, total hip or femoral neck at any time point during the extension treatment period was 2% with continuous ORILISSA 150 mg once daily and 21% with continuous ORILISSA 200 mg twice daily.


Table 3. Percent Change from Baseline in Lumbar Spine BMD at Month 6
ORILISSA       ORILISSA
150 mg         200 mg
Once Daily    Twice Daily              Placebo
EM-1
N                                                 183            180                   277 Percent Change from Baseline, %                   -0.3           -2.6                  0.5 -0.9           -3.1
Treatment Difference, % (95% CI)
(-1.3, -0.4)   (-3.6, -2.6)
EM-2
N                                                 174            183                   271 Percent Change from Baseline, %                   -0.7           -2.5                  0.6 -1.3           -3.0
Treatment Difference, % (95% CI)
(-1.8, -0.8)   (-3.5, -2.6)
To assess for recovery, 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 (Figure 1).
In Study EM-3, if a subject had BMD loss of more than 1.5% at the lumbar spine or more than 2.5% at the total hip at the end of treatment, follow-up DXA was required after 6 months off- treatment. In Study EM-4, all subjects were required to have a follow-up DXA 6 months off treatment regardless of change in BMD and if a subject had BMD loss of more than 1.5% at the lumbar spine or more than 2.5% at the total hip after 6 months off treatment, follow-up DXA was required after 12 months off-treatment. Figure 2 shows the change in lumbar spine BMD for the subjects in Study EM-2/EM-4 who completed 12 months of treatment with ORILISSA and who had a follow-up DXA 12-months off treatment.

Figure 1. 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



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Figure 2. 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



Suicidal Ideation, Suicidal Behavior and Exacerbation of Mood Disorders In the placebo-controlled trials (Studies EM-1 and EM-2), ORILISSA was associated with adverse mood changes (see Table 2 and Table 4), particularly in those with a history of depression.

Table 4. Suicidal Ideation and Suicidal Behavior in Studies EM-1 and EM-2 ORILISSA
150 mg              200 mg
Once Daily           Twice Daily                  Placebo
(N=475)             (N=477)                     (N=734)
Adverse Reactions                          n (%)               n (%)                      n (%) Completed suicide                         1 (0.2)                 0                          0 Suicidal ideation                         1 (0.2)             1 (0.2)                        0 A 44-year-old woman received 31 days of ORILISSA 150 mg once daily then completed suicide 2 days after ORILISSA discontinuation. She had no relevant past medical history; life stressors were noted.
Among the 2090 subjects exposed to ORILISSA in the endometriosis Phase 2 and Phase 3 studies, there were four reports of suicidal ideation. In addition to the two subjects in Table 4, there were two additional reports of suicidal ideation: one subject in EM-3 (150 mg once daily) and one in a Phase 2 study (75 mg once daily, an unapproved dose). Three of these subjects had a history of depression. Two subjects discontinued ORILISSA and two completed the clinical trial treatment periods.
Hepatic Transaminase Elevations
In the placebo-controlled clinical trials (Studies EM-1 and EM-2), dose-dependent asymptomatic elevations of serum 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).
Changes in Lipid Parameters
Dose-dependent increases in total cholesterol, low-density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), and serum triglycerides were noted during ORILISSA treatment in EM-1 and EM-2. In EM-1 and EM-2, 12% and 1% of subjects with mildly elevated LDL-C (130-159 mg/dL) at baseline had an increase in LDL-C concentrations to 190 mg/dL or higher during treatment with ORILISSA and placebo, respectively. In EM-1 and EM-2, 4% and 1% of subjects with mildly elevated serum triglycerides (150-300 mg/dL) at baseline had an increase in serum triglycerides to at least 500 mg/dL during treatment with ORILISSA and placebo, respectively. The highest measured serum triglyceride concentration during treatment with ORILISSA was 982 mg/dL.


Table 5. Mean Change and Maximum Increase from Baseline in Serum Lipids in Studies EM-1 and EM-2
ORILISSA           ORILISSA
150 mg            200 mg
Once Daily        Twice Daily      Placebo
N=475             N=477          N=734
LDL-C (mg/dL)
Mean change at Month 6                      5                13             -3 Maximum increase during
Treatment Period                          137               107            122 HDL-C (mg/dL)
Mean change at Month 6                      2                 4              1 Maximum increase during
Treatment Period                           43                52             45 Triglycerides (mg/dL)
Mean change at Month 6                    <1                 11             -3 Maximum increase during
Treatment Period                          624               484            440 Lipid increases occurred within 1 to 2 months after the start of ORILISSA and remained stable thereafter over 12 months.


Hypersensitivity Reactions
In Studies EM-1 and EM-2, non-serious hypersensitivity reactions including rash occurred in 5.8% of ORILISSA treated-subjects and 6.1% of placebo-treated subjects. These events led to study drug discontinuation in 0.4% of ORILISSA-treated subjects and 0.5% of placebo-treated subjects.
Effects on menstrual bleeding patterns
The effects of ORILISSA on menstrual bleeding were evaluated for up to 12 months using an electronic daily diary where subjects classified their flow of menstrual bleeding (if present in the last 24 hours) as spotting, light, medium, or heavy. ORILISSA led to a dose-dependent reduction in mean number of bleeding and spotting days and bleeding intensity in those subjects who reported menstrual bleeding.


Table 6. Mean Bleeding/Spotting Days and Mean Intensity Scores at Month 3 ORILISSA                    ORILISSA
Placebo
150mg Once Daily           200mg Twice Daily
Baseline     Month 3       Baseline      Month 3       Baseline Month 3 Mean bleeding/ spotting days             5.3          2.8           5.7           0.8          5.4          4.6 in prior 28 days
Mean Intensity
2.6          2.2           2.5           2.0          2.6          2.4 scorea a
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 
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.
The incidence of amenorrhea during the first six months of treatment ranged from 6-17% for ORILISSA 150 mg once daily, 13-52% for ORILISSA 200 mg twice daily and less than 1% for placebo. During the second 6 months of treatment, the incidence of amenorrhea ranged from 11- 15% for ORILISSA 150 mg once daily and 46-57% for ORILISSA 200 mg twice daily.
After 6 months of therapy with ORILISSA 150 mg once daily, resumption of menses after stopping treatment was reported by 59%, 87% and 95% of women within 1, 2, and 6 months, respectively. After 6 months of therapy with ORILISSA 200 mg twice daily, resumption of menses after stopping treatment was reported by 60%, 88%, and 97% of women within 1, 2, and 6 months, respectively.
After 12 months of therapy with ORILISSA 150 mg once daily resumption of menses after stopping treatment was reported by 77%, 95% and 98% of women within 1, 2, and 6 months respectively. After 12 months of therapy with ORILISSA 200 mg twice daily resumption of menses after stopping treatment was reported by 55%, 91% and 96% of women within 1, 2, and 6 months respectively.



7.2 Postmarketing Experience
The following adverse reactions have been identified during post-approval use of ORILISSA.
Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Immune system disorders: hypersensitivity reactions (including anaphylaxis, angioedema, and urticaria).
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorization of the medicinal product is important.
It allows continued monitoring of the benefit/risk balance of the medicinal product.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il