Orilissa
(Elagolix)Dosage & Administration
Dosing Regimen | Maximum Treatment Duration | Coexisting Condition |
| Initiate treatment with ORILISSA 150 mg once daily | 24 months | None |
| Consider initiating treatment with ORILISSA 200 mg twice daily | 6 months | Dyspareunia |
| Initiate treatment with ORILISSA 150 mg once daily. Use of 200 mg twice daily is not recommended. | 6 months | Moderate hepatic impairment (Child-Pugh Class B) |
Dosing Regimen | Maximum Treatment Duration | Coexisting Condition |
| Initiate treatment with ORILISSA 150 mg once daily | 24 months | None |
| Consider initiating treatment with ORILISSA 200 mg twice daily | 6 months | Dyspareunia |
| Initiate treatment with ORILISSA 150 mg once daily. Use of 200 mg twice daily is not recommended. | 6 months | Moderate hepatic impairment (Child-Pugh Class B) |
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Orilissa Prescribing Information
ORILISSA is indicated for the management of moderate to severe pain associated with endometriosis.
Limit the duration of use based on the dose and coexisting condition (see
Dosing Regimen | Maximum Treatment Duration | Coexisting Condition |
| Initiate treatment with ORILISSA 150 mg once daily | 24 months | None |
| Consider initiating treatment with ORILISSA 200 mg twice daily | 6 months | Dyspareunia |
| Initiate treatment with ORILISSA 150 mg once daily. Use of 200 mg twice daily is not recommended. | 6 months | Moderate hepatic impairment (Child-Pugh Class B) |
- Exclude pregnancy before starting ORILISSA or start ORILISSA within 7 days from the onset of menses.
- Take ORILISSA at approximately the same time each day, with or without food.
- Use the lowest effective dose, taking into account the severity of symptoms and treatment objectives[see Warnings and Precautions (5.1,5.3,5.4) and Clinical Studies (14)].
- Limit the duration of use because of bone loss [see Warnings and Precautions (5.1)].
Dosing Regimen | Maximum Treatment Duration | Coexisting Condition |
| Initiate treatment with ORILISSA 150 mg once daily | 24 months | None |
| Consider initiating treatment with ORILISSA 200 mg twice daily | 6 months | Dyspareunia |
| Initiate treatment with ORILISSA 150 mg once daily. Use of 200 mg twice daily is not recommended. | 6 months | Moderate hepatic impairment (Child-Pugh Class B) |
ORILISSA causes a dose-dependent decrease in bone mineral density (BMD). BMD loss is greater with increasing duration of use and may not be completely reversible after stopping treatment
ORILISSA is contraindicated in women with known osteoporosis
- Exclude pregnancy before starting ORILISSA or start ORILISSA within 7 days from the onset of menses.
- Take ORILISSA at approximately the same time each day, with or without food.
- Use the lowest effective dose, taking into account the severity of symptoms and treatment objectives[see Warnings and Precautions (5.1,5.3,5.4) and Clinical Studies (14)].
- Limit the duration of use because of bone loss [see Warnings and Precautions (5.1)].
Dosing Regimen | Maximum Treatment Duration | Coexisting Condition |
| Initiate treatment with ORILISSA 150 mg once daily | 24 months | None |
| Consider initiating treatment with ORILISSA 200 mg twice daily | 6 months | Dyspareunia |
| Initiate treatment with ORILISSA 150 mg once daily. Use of 200 mg twice daily is not recommended. | 6 months | Moderate hepatic impairment (Child-Pugh Class B) |
- Exclude pregnancy before starting ORILISSA or start ORILISSA within 7 days from the onset of menses.
- Take ORILISSA at approximately the same time each day, with or without food.
- Use the lowest effective dose, taking into account the severity of symptoms and treatment objectives[see Warnings and Precautions (5.1,5.3,5.4) and Clinical Studies (14)].
- Limit the duration of use because of bone loss [see Warnings and Precautions (5.1)].
Dosing Regimen | Maximum Treatment Duration | Coexisting Condition |
| Initiate treatment with ORILISSA 150 mg once daily | 24 months | None |
| Consider initiating treatment with ORILISSA 200 mg twice daily | 6 months | Dyspareunia |
| Initiate treatment with ORILISSA 150 mg once daily. Use of 200 mg twice daily is not recommended. | 6 months | Moderate hepatic impairment (Child-Pugh Class B) |
The 150 mg tablets are light pink, oblong, film-coated tablets with “EL 150” debossed on one side. Each tablet contains 155.2 mg of elagolix sodium equivalent to 150 mg of elagolix.
The 200 mg tablets are light orange, oblong, film-coated tablets with “EL 200” debossed on one side. Each tablet contains 207.0 mg of elagolix sodium equivalent to 200 mg of elagolix.
There is a pregnancy registry that monitors pregnancy outcomes in women exposed to ORILISSA during pregnancy. Healthcare providers are encouraged to register patients, or pregnant women may enroll themselves in the registry by calling 1-833-782-7241 or visiting https://www.bloompregnancyregistry.com.
Use of ORILISSA is contraindicated in pregnant women. Exposure to ORILISSA early in pregnancy may increase the risk of early pregnancy loss. Discontinue ORILISSA if pregnancy occurs during treatment.
The limited human data with the use of ORILISSA in pregnant women are insufficient to determine whether there is a risk for major birth defects or miscarriage. Although two cases of congenital malformations were reported in clinical trials with ORILISSA, no pattern was identified and miscarriages were reported at a similar incidence across treatment groups
There is a pregnancy registry that monitors pregnancy outcomes in women exposed to ORILISSA during pregnancy. Healthcare providers are encouraged to register patients, or pregnant women may enroll themselves in the registry by calling 1-833-782-7241 or visiting https://www.bloompregnancyregistry.com.
Use of ORILISSA is contraindicated in pregnant women. Exposure to ORILISSA early in pregnancy may increase the risk of early pregnancy loss. Discontinue ORILISSA if pregnancy occurs during treatment.
The limited human data with the use of ORILISSA in pregnant women are insufficient to determine whether there is a risk for major birth defects or miscarriage. Although two cases of congenital malformations were reported in clinical trials with ORILISSA, no pattern was identified and miscarriages were reported at a similar incidence across treatment groups
When pregnant rats and rabbits were orally dosed with elagolix during the period of organogenesis, postimplantation loss was observed in pregnant rats at doses 20 times the maximum recommended human dose (MRHD). Spontaneous abortion and total litter loss was observed in rabbits at doses 7 and 12 times the MRHD. There were no structural abnormalities in the fetuses at exposures up to 40 and 12 times the MRHD for the rat and rabbit, respectively
There were 49 pregnancies reported in clinical trials of more than 3,500 women (of whom more than 2,000 had endometriosis) treated with ORILISSA for up to 12 months. These pregnancies occurred while the women were receiving ORILISSA or within 30 days after stopping ORILISSA. Among these 49 pregnancies, two major congenital malformations were reported. In one case of infant cleft palate, the mother was treated with ORILISSA 150 mg daily and the estimated fetal exposure to ORILISSA occurred during the first 30 days of pregnancy. In one case of infant tracheoesophageal fistula, the mother was treated with ORILISSA 150 mg daily and the estimated fetal exposure to ORILISSA occurred during the first 15 days of pregnancy.
Among these 49 pregnancies, there were five cases of spontaneous abortion (miscarriage) compared to five cases among the 20 pregnancies that occurred in more than 1100 women treated with placebo. Although the duration of fetal exposure was limited in ORILISSA clinical trials, there were no apparent decreases in birth weights associated with ORILISSA in comparison to placebo.
Embryofetal development studies were conducted in the rat and rabbit. Elagolix was administered by oral gavage to pregnant rats (25 animals/dose) at doses of 0, 300, 600 and 1200 mg/kg/day and to rabbits (20 animals/dose) at doses of 0, 100, 150, and 200 mg/kg/day, during the period of organogenesis (gestation day 6-17 in the rat and gestation day 7-20 in the rabbit).
In rats, maternal toxicity was present at all doses and included six deaths and decreases in body weight gain and food consumption. Increased postimplantation losses were present in the mid dose group, which was 20 times the MRHD based on AUC. In rabbits, three spontaneous abortions and a single total litter loss were observed at the highest, maternally toxic dose, which was 12 times the MRHD based on AUC. A single total litter loss occurred at a lower non-maternally toxic dose of 150 mg/kg/day, which was 7 times the MRHD.
No fetal malformations were present at any dose level tested in either species even in the presence of maternal toxicity. At the highest doses tested, the exposure margins were 40 and 12 times the MRHD for the rat and rabbit, respectively. However, because elagolix binds poorly to the rat gonadotropin-releasing hormone (GnRH) receptor (~1000 fold less than to the human GnRH receptor), the rat study is unlikely to identify pharmacologically mediated effects of elagolix on embryofetal development. The rat study is still expected to provide information on potential non-target-related effects of elagolix.
In a pre- and postnatal development study in rats, elagolix was given in the diet to achieve doses of 0, 100 and 300 mg/kg/day (25 per dose group) from gestation day 6 to lactation day 20. There was no evidence of maternal toxicity. At the highest dose, two dams had total litter loss, and one failed to deliver. Pup survival was decreased from birth to postnatal day 4. Pups had lower birth weights and lower body weight gains were observed throughout the pre-weaning period at 300 mg/kg/day. Smaller body size and effect on startle response were associated with lower pup weights at 300 mg/kg/day. Post-weaning growth, development and behavioral endpoints were unaffected.
Maternal plasma concentrations in rats on lactation day 21 at 100 and 300 mg/kg/day (47 and 125 ng/mL) were 0.06-fold and 0.16-fold the maximal elagolix concentration (Cmax) in humans at the MRHD. Because the exposures achieved in rats were much lower than the human MRHD, this study is not predictive of potentially higher lactational exposure in humans.
When pregnant rats and rabbits were orally dosed with elagolix during the period of organogenesis, postimplantation loss was observed in pregnant rats at doses 20 times the maximum recommended human dose (MRHD). Spontaneous abortion and total litter loss was observed in rabbits at doses 7 and 12 times the MRHD. There were no structural abnormalities in the fetuses at exposures up to 40 and 12 times the MRHD for the rat and rabbit, respectively
There is a pregnancy registry that monitors pregnancy outcomes in women exposed to ORILISSA during pregnancy. Healthcare providers are encouraged to register patients, or pregnant women may enroll themselves in the registry by calling 1-833-782-7241 or visiting https://www.bloompregnancyregistry.com.
Use of ORILISSA is contraindicated in pregnant women. Exposure to ORILISSA early in pregnancy may increase the risk of early pregnancy loss. Discontinue ORILISSA if pregnancy occurs during treatment.
The limited human data with the use of ORILISSA in pregnant women are insufficient to determine whether there is a risk for major birth defects or miscarriage. Although two cases of congenital malformations were reported in clinical trials with ORILISSA, no pattern was identified and miscarriages were reported at a similar incidence across treatment groups
When pregnant rats and rabbits were orally dosed with elagolix during the period of organogenesis, postimplantation loss was observed in pregnant rats at doses 20 times the maximum recommended human dose (MRHD). Spontaneous abortion and total litter loss was observed in rabbits at doses 7 and 12 times the MRHD. There were no structural abnormalities in the fetuses at exposures up to 40 and 12 times the MRHD for the rat and rabbit, respectively
There were 49 pregnancies reported in clinical trials of more than 3,500 women (of whom more than 2,000 had endometriosis) treated with ORILISSA for up to 12 months. These pregnancies occurred while the women were receiving ORILISSA or within 30 days after stopping ORILISSA. Among these 49 pregnancies, two major congenital malformations were reported. In one case of infant cleft palate, the mother was treated with ORILISSA 150 mg daily and the estimated fetal exposure to ORILISSA occurred during the first 30 days of pregnancy. In one case of infant tracheoesophageal fistula, the mother was treated with ORILISSA 150 mg daily and the estimated fetal exposure to ORILISSA occurred during the first 15 days of pregnancy.
Among these 49 pregnancies, there were five cases of spontaneous abortion (miscarriage) compared to five cases among the 20 pregnancies that occurred in more than 1100 women treated with placebo. Although the duration of fetal exposure was limited in ORILISSA clinical trials, there were no apparent decreases in birth weights associated with ORILISSA in comparison to placebo.
Embryofetal development studies were conducted in the rat and rabbit. Elagolix was administered by oral gavage to pregnant rats (25 animals/dose) at doses of 0, 300, 600 and 1200 mg/kg/day and to rabbits (20 animals/dose) at doses of 0, 100, 150, and 200 mg/kg/day, during the period of organogenesis (gestation day 6-17 in the rat and gestation day 7-20 in the rabbit).
In rats, maternal toxicity was present at all doses and included six deaths and decreases in body weight gain and food consumption. Increased postimplantation losses were present in the mid dose group, which was 20 times the MRHD based on AUC. In rabbits, three spontaneous abortions and a single total litter loss were observed at the highest, maternally toxic dose, which was 12 times the MRHD based on AUC. A single total litter loss occurred at a lower non-maternally toxic dose of 150 mg/kg/day, which was 7 times the MRHD.
No fetal malformations were present at any dose level tested in either species even in the presence of maternal toxicity. At the highest doses tested, the exposure margins were 40 and 12 times the MRHD for the rat and rabbit, respectively. However, because elagolix binds poorly to the rat gonadotropin-releasing hormone (GnRH) receptor (~1000 fold less than to the human GnRH receptor), the rat study is unlikely to identify pharmacologically mediated effects of elagolix on embryofetal development. The rat study is still expected to provide information on potential non-target-related effects of elagolix.
In a pre- and postnatal development study in rats, elagolix was given in the diet to achieve doses of 0, 100 and 300 mg/kg/day (25 per dose group) from gestation day 6 to lactation day 20. There was no evidence of maternal toxicity. At the highest dose, two dams had total litter loss, and one failed to deliver. Pup survival was decreased from birth to postnatal day 4. Pups had lower birth weights and lower body weight gains were observed throughout the pre-weaning period at 300 mg/kg/day. Smaller body size and effect on startle response were associated with lower pup weights at 300 mg/kg/day. Post-weaning growth, development and behavioral endpoints were unaffected.
Maternal plasma concentrations in rats on lactation day 21 at 100 and 300 mg/kg/day (47 and 125 ng/mL) were 0.06-fold and 0.16-fold the maximal elagolix concentration (Cmax) in humans at the MRHD. Because the exposures achieved in rats were much lower than the human MRHD, this study is not predictive of potentially higher lactational exposure in humans.
There were 49 pregnancies reported in clinical trials of more than 3,500 women (of whom more than 2,000 had endometriosis) treated with ORILISSA for up to 12 months. These pregnancies occurred while the women were receiving ORILISSA or within 30 days after stopping ORILISSA. Among these 49 pregnancies, two major congenital malformations were reported. In one case of infant cleft palate, the mother was treated with ORILISSA 150 mg daily and the estimated fetal exposure to ORILISSA occurred during the first 30 days of pregnancy. In one case of infant tracheoesophageal fistula, the mother was treated with ORILISSA 150 mg daily and the estimated fetal exposure to ORILISSA occurred during the first 15 days of pregnancy.
Among these 49 pregnancies, there were five cases of spontaneous abortion (miscarriage) compared to five cases among the 20 pregnancies that occurred in more than 1100 women treated with placebo. Although the duration of fetal exposure was limited in ORILISSA clinical trials, there were no apparent decreases in birth weights associated with ORILISSA in comparison to placebo.
Embryofetal development studies were conducted in the rat and rabbit. Elagolix was administered by oral gavage to pregnant rats (25 animals/dose) at doses of 0, 300, 600 and 1200 mg/kg/day and to rabbits (20 animals/dose) at doses of 0, 100, 150, and 200 mg/kg/day, during the period of organogenesis (gestation day 6-17 in the rat and gestation day 7-20 in the rabbit).
In rats, maternal toxicity was present at all doses and included six deaths and decreases in body weight gain and food consumption. Increased postimplantation losses were present in the mid dose group, which was 20 times the MRHD based on AUC. In rabbits, three spontaneous abortions and a single total litter loss were observed at the highest, maternally toxic dose, which was 12 times the MRHD based on AUC. A single total litter loss occurred at a lower non-maternally toxic dose of 150 mg/kg/day, which was 7 times the MRHD.
No fetal malformations were present at any dose level tested in either species even in the presence of maternal toxicity. At the highest doses tested, the exposure margins were 40 and 12 times the MRHD for the rat and rabbit, respectively. However, because elagolix binds poorly to the rat gonadotropin-releasing hormone (GnRH) receptor (~1000 fold less than to the human GnRH receptor), the rat study is unlikely to identify pharmacologically mediated effects of elagolix on embryofetal development. The rat study is still expected to provide information on potential non-target-related effects of elagolix.
In a pre- and postnatal development study in rats, elagolix was given in the diet to achieve doses of 0, 100 and 300 mg/kg/day (25 per dose group) from gestation day 6 to lactation day 20. There was no evidence of maternal toxicity. At the highest dose, two dams had total litter loss, and one failed to deliver. Pup survival was decreased from birth to postnatal day 4. Pups had lower birth weights and lower body weight gains were observed throughout the pre-weaning period at 300 mg/kg/day. Smaller body size and effect on startle response were associated with lower pup weights at 300 mg/kg/day. Post-weaning growth, development and behavioral endpoints were unaffected.
Maternal plasma concentrations in rats on lactation day 21 at 100 and 300 mg/kg/day (47 and 125 ng/mL) were 0.06-fold and 0.16-fold the maximal elagolix concentration (Cmax) in humans at the MRHD. Because the exposures achieved in rats were much lower than the human MRHD, this study is not predictive of potentially higher lactational exposure in humans.
ORILISSA is contraindicated in women:
● Who are pregnant
There is a pregnancy registry that monitors pregnancy outcomes in women exposed to ORILISSA during pregnancy. Healthcare providers are encouraged to register patients, or pregnant women may enroll themselves in the registry by calling 1-833-782-7241 or visiting https://www.bloompregnancyregistry.com.
Use of ORILISSA is contraindicated in pregnant women. Exposure to ORILISSA early in pregnancy may increase the risk of early pregnancy loss. Discontinue ORILISSA if pregnancy occurs during treatment.
The limited human data with the use of ORILISSA in pregnant women are insufficient to determine whether there is a risk for major birth defects or miscarriage. Although two cases of congenital malformations were reported in clinical trials with ORILISSA, no pattern was identified and miscarriages were reported at a similar incidence across treatment groups
When pregnant rats and rabbits were orally dosed with elagolix during the period of organogenesis, postimplantation loss was observed in pregnant rats at doses 20 times the maximum recommended human dose (MRHD). Spontaneous abortion and total litter loss was observed in rabbits at doses 7 and 12 times the MRHD. There were no structural abnormalities in the fetuses at exposures up to 40 and 12 times the MRHD for the rat and rabbit, respectively
There were 49 pregnancies reported in clinical trials of more than 3,500 women (of whom more than 2,000 had endometriosis) treated with ORILISSA for up to 12 months. These pregnancies occurred while the women were receiving ORILISSA or within 30 days after stopping ORILISSA. Among these 49 pregnancies, two major congenital malformations were reported. In one case of infant cleft palate, the mother was treated with ORILISSA 150 mg daily and the estimated fetal exposure to ORILISSA occurred during the first 30 days of pregnancy. In one case of infant tracheoesophageal fistula, the mother was treated with ORILISSA 150 mg daily and the estimated fetal exposure to ORILISSA occurred during the first 15 days of pregnancy.
Among these 49 pregnancies, there were five cases of spontaneous abortion (miscarriage) compared to five cases among the 20 pregnancies that occurred in more than 1100 women treated with placebo. Although the duration of fetal exposure was limited in ORILISSA clinical trials, there were no apparent decreases in birth weights associated with ORILISSA in comparison to placebo.
Embryofetal development studies were conducted in the rat and rabbit. Elagolix was administered by oral gavage to pregnant rats (25 animals/dose) at doses of 0, 300, 600 and 1200 mg/kg/day and to rabbits (20 animals/dose) at doses of 0, 100, 150, and 200 mg/kg/day, during the period of organogenesis (gestation day 6-17 in the rat and gestation day 7-20 in the rabbit).
In rats, maternal toxicity was present at all doses and included six deaths and decreases in body weight gain and food consumption. Increased postimplantation losses were present in the mid dose group, which was 20 times the MRHD based on AUC. In rabbits, three spontaneous abortions and a single total litter loss were observed at the highest, maternally toxic dose, which was 12 times the MRHD based on AUC. A single total litter loss occurred at a lower non-maternally toxic dose of 150 mg/kg/day, which was 7 times the MRHD.
No fetal malformations were present at any dose level tested in either species even in the presence of maternal toxicity. At the highest doses tested, the exposure margins were 40 and 12 times the MRHD for the rat and rabbit, respectively. However, because elagolix binds poorly to the rat gonadotropin-releasing hormone (GnRH) receptor (~1000 fold less than to the human GnRH receptor), the rat study is unlikely to identify pharmacologically mediated effects of elagolix on embryofetal development. The rat study is still expected to provide information on potential non-target-related effects of elagolix.
In a pre- and postnatal development study in rats, elagolix was given in the diet to achieve doses of 0, 100 and 300 mg/kg/day (25 per dose group) from gestation day 6 to lactation day 20. There was no evidence of maternal toxicity. At the highest dose, two dams had total litter loss, and one failed to deliver. Pup survival was decreased from birth to postnatal day 4. Pups had lower birth weights and lower body weight gains were observed throughout the pre-weaning period at 300 mg/kg/day. Smaller body size and effect on startle response were associated with lower pup weights at 300 mg/kg/day. Post-weaning growth, development and behavioral endpoints were unaffected.
Maternal plasma concentrations in rats on lactation day 21 at 100 and 300 mg/kg/day (47 and 125 ng/mL) were 0.06-fold and 0.16-fold the maximal elagolix concentration (Cmax) in humans at the MRHD. Because the exposures achieved in rats were much lower than the human MRHD, this study is not predictive of potentially higher lactational exposure in humans.
● With known osteoporosis because of the risk of further bone loss
ORILISSA causes a dose-dependent decrease in bone mineral density (BMD). BMD loss is greater with increasing duration of use and may not be completely reversible after stopping treatment
ORILISSA is contraindicated in women with known osteoporosis
● With severe hepatic impairment
No dosage adjustment of ORILISSA is required for women with mild hepatic impairment (Child-Pugh A). Only the 150 mg once daily regimen is recommended for women with moderate hepatic impairment (Child-Pugh B) and the duration of treatment should be limited to 6 months.
ORILISSA is contraindicated in women with severe hepatic impairment (Child-Pugh C)
The pharmacokinetic properties of ORILISSA in healthy subjects are summarized in Table 8. The steady state pharmacokinetic parameters under fasting conditions are summarized in Table 9.
Absorption | |
| Tmax(h) | 1.0 |
| Effect of high-fat meal (relative to fasting) | AUC: ↓24%, Cmax: ↓36% |
Distribution | |
| % Bound to human plasma proteins | 80 |
| Blood-to-plasma ratio | 0.6 |
Metabolism | |
| Metabolism | CYP3A (major) Minor pathways include: CYP2D6, CYP2C8, and uridine glucuronosyl transferases (UGTs) |
Elimination | |
| Major route of elimination | Hepatic metabolism |
| Terminal phase elimination half-life (t1/2) (h) | 4-6 |
| % of dose excreted in urine | <3 |
| % of dose excreted in feces | 90 |
Pharmacokinetic Parameter (Units) | 150 mg Once Daily N = 6 | 200 mg Twice Daily N = 7 |
C max (ng/mL) | 574 (29) | 774 (68) |
AUC τ (ng●hr/mL) | 1292 (31) | 1725 (57) |
CL/F (L/hr) | 123 (21) | 144 (43) |
V dss /F | 1674 (94) | 881 (38) |
R ac | 0.98 (7) | 0.89 (19) |
| CV: Coefficient of variation Cmax: peak concentration AUCτ: area under the plasma concentration-time curve during the dosing interval (τ) i.e., 12 hours for twice daily regimen, 24 hours for once daily regimen. CL/F: oral clearance Vdss/F: apparent volume of distribution at steady state Rac: drug accumulation ratio | ||
Elagolix exposures (Cmaxand AUC) are not altered by renal impairment. The mean exposures are similar for women with moderate to severe or end stage renal disease (including women on dialysis) compared to women with normal renal function.
Elagolix exposures (Cmaxand AUC) are similar between women with normal hepatic function and women with mild hepatic impairment. Elagolix exposures in women with moderate and severe hepatic impairment are approximately 3-fold and 7-fold, respectively, higher than exposures from women with normal hepatic function
No clinically meaningful difference in the pharmacokinetics of ORILISSA between White and Black subjects or between Hispanics and others was observed. There is no clinically meaningful difference in the pharmacokinetics of ORILISSA between Japanese and Han Chinese subjects.
Body weight or body mass index does not affect the pharmacokinetics of ORILISSA.
Drug interaction studies were performed with ORILISSA and other drugs that are likely to be co-administered and with drugs commonly used as probes for pharmacokinetic interactions. Tables 10and 11summarize the pharmacokinetic effects when elagolix was co-administered with these drugs.
Co- administered Drug | Regimen of Co- administered Drug | Regimen of Elagolix | N | Ratio (90% CI)* | |
| Ketoconazole | 400 mg once daily | 150 mg single dose | 11 | C max | AUC |
| 1.77 (1.48 – 2.12) | 2.20 (1.98 – 2.44) | ||||
| Rifampin# | 600 mg single dose | 150 mg single dose | 12 | 4.37 (3.62 – 5.28) | 5.58 (4.88 – 6.37) |
| 600 mg once daily | 2.00 (1.66 – 2.41) | 1.65 (1.45 – 1.89) | |||
| CI: Confidence interval *ratios for Cmaxand AUC compare co-administration of the medication with elagolix vs. administration of elagolix alone. #A single dose of 600 mg rifampin inhibits OATP1B1; 600 mg once daily dose of rifampin inhibits OATP1B1 and induces CYP3A. | |||||
No clinically significant changes in elagolix exposures were observed when co-administered with rosuvastatin (20 mg once daily), sertraline (25 mg once daily) or fluconazole (200 mg single dose).
Co- administered Drug | Regimen of Co- administered Drug | Regimen of Elagolix | N | Ratio (90% CI)* | |
| Digoxin | 0.5 mg single dose | 200 mg twice daily x 10 days | 11 | C max | AUC |
| 1.71 (1.53 – 1.91) | 1.26 (1.17 – 1.35) | ||||
| Rosuvastatin | 20 mg once daily | 300 mg twice daily x 7 days | 10 | 0.99 (0.73 – 1.35) | 0.60 (0.50 – 0.71) |
| Midazolam | 2 mg single dose | 300 mg twice daily x 11 days | 20 | 0.56 (0.51 – 0.62) | 0.46 (0.41 – 0.50) |
| 150 mg once daily x 13 days | 11 | 0.81 (0.74 – 0.89) | 0.65 (0.58 – 0.72) | ||
| Norethindrone | 0.35 mg once daily x 112 days | 150 mg once daily x 56 days | 32 | 0.95 (0.86 – 1.05) | 0.88 (0.79 – 0.99) |
| Ethinyl Estradiol | Ethinyl estradiol 35 mcg and triphasic norgestimate 0.18/0.215/0.25 mg once daily | 150 mg once daily | 21 | 1.15 (1.07 – 1.25) | 1.30 (1.19 – 1.42) |
| Norelgestromina | 0.87 (0.78 – 0.97) | 0.85 (0.78 – 0.92) | |||
| Norgestrela | 0.89 (0.78 – 1.00) | 0.92 (0.84 – 1.01) | |||
| Ethinyl Estradiol | Ethinyl estradiol 20 mcg/Levonorgestrel 0.1 mg single dose | 200 mg twice daily x 15 days | 20 | 1.36 (1.27 – 1.45) | 2.18 (1.99 – 2.39) |
| Levonorgestrel | 0.97 (0.88 – 1.07) | 0.73 (0.64 – 0.82) | |||
| Omeprazole | 40 mg single dose | 300 mg twice daily x 9 days | 20 | 1.95 (1.50 – 2.53) | 1.78 (1.39 – 2.27) |
| CI: Confidence interval *ratios for Cmaxand AUC compare co-administration of the medication with elagolix vs. administration of the medication alone. ametabolite of norgestimate | |||||
No clinically significant changes were observed in exposures of sertraline, fluconazole, or bupropion when co-administered with elagolix 300 mg twice daily.
● Taking inhibitors of organic anion transporting polypeptide (OATP)1B1 (a hepatic uptake transporter) that are known or expected to significantly increase elagolix plasma concentrations
Elagolix is a substrate of CYP3A, P-gp, and OATP1B1.
Concomitant use of ORILISSA 200 mg twice daily and strong CYP3A inhibitors for more than 1 month is not recommended. Limit concomitant use of ORILISSA 150 mg once daily and strong CYP3A inhibitors to 6 months.
Co-administration of ORILISSA with strong CYP3A inducers may decrease elagolix plasma concentrations and may result in a decrease of the therapeutic effects of ORILISSA.
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.
The effect of concomitant use of P-gp inhibitors or inducers on the pharmacokinetics of ORILISSA is unknown. OATP1B1 inhibitors that are known or expected to significantly increase elagolix plasma concentrations are contraindicated due to increased risk of elagolix-associated adverse reactions
● With known hypersensitivity reaction to ORILISSA or any of its inactive components. Reactions have included anaphylaxis and angioedema
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).
- Bone Loss: Dose- and duration-dependent decreases in bone mineral density (BMD) that may not be completely reversible. Assess BMD in women with additional risk factors for bone loss ()5.1 Bone Loss
ORILISSA causes a dose-dependent decrease in bone mineral density (BMD). BMD loss is greater with increasing duration of use and may not be completely reversible after stopping treatment
[see Adverse Reactions (6.1)]. The impact of these BMD decreases on long-term bone health and future fracture risk are unknown.ORILISSA is contraindicated in women with known osteoporosis
[see Contraindications (4)].Consider assessment of BMD in patients with a history of a low-trauma fracture or other risk factors for osteoporosis or bone loss. Limit the duration of use to reduce the extent of bone loss[see Dosage and Administration (2.2)].Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial for all patients. - Reduced Ability to Recognize Pregnancy: ORILISSA may alter menstrual bleeding, which may reduce the ability to recognize pregnancy. Perform testing if pregnancy is suspected. Discontinue if pregnancy is confirmed ()5.2 Change in Menstrual Bleeding Pattern and Reduced Ability to Recognize Pregnancy
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
[see Adverse Reactions (6.1)]. Perform pregnancy testing if pregnancy is suspected, and discontinue ORILISSA if pregnancy is confirmed. - Suicidal Ideation and Mood Disorders: Advise patients to seek medical attention for suicidal ideation, suicidal behavior, new onset or worsening depression, anxiety, or other mood changes ()5.3 Suicidal Ideation, Suicidal Behavior, and Exacerbation of Mood Disorders
Suicidal ideation and behavior, including one completed suicide, occurred in subjects treated with ORILISSA in the endometriosis clinical trials. ORILISSA subjects had a higher incidence of depression and mood changes compared to placebo, and ORILISSA subjects with a history of suicidality or depression had a higher incidence of depression compared to subjects without such a history
[see Adverse Reactions (6.1)]. Promptly evaluate patients with depressive symptoms to determine whether the risks of continued therapy outweigh the benefits[see Adverse Reactions (6.1)]. 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. - Hepatic Transaminase Elevations: Dose-dependent elevations in serum alanine aminotransferase (ALT). Counsel patients on signs and symptoms of liver injury ()5.4 Hepatic Transaminase Elevations
In clinical trials, dose-dependent elevations of serum alanine aminotransferase (ALT) at least 3-times the upper limit of the reference range occurred with ORILISSA. Use the lowest effective dose of ORILISSA 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 elevations in liver tests to determine whether the benefits of continued therapy outweigh the risks
[see Adverse Reactions (6.1)]. - Interactions with Hormonal Contraceptives: Use non-hormonal contraception during treatment and for 28 days after discontinuing ORILISSA. Coadministration of ORILISSA 200 mg twice daily with an estrogen-containing contraceptive is not recommended because of the potential for increased estrogen-associated risks. Coadministration of ORILISSA with an estrogen-containing contraceptive may reduce the efficacy of ORILISSA. Coadministration with progestin-containing oral contraceptives may reduce the efficacy of the contraceptive. ()5.5 Interactions with Hormonal Contraceptives
Advise women to use effective non-hormonal contraceptives during treatment with ORILISSA and for 28 days after discontinuing ORILISSA
[see Use in Specific Populations (8.1,8.3), Drug Interactions (7.1), Clinical Pharmacology (12.3)].Increase in Estrogen Exposure andPotentialAssociatedIncreasedRisks WhenORILISSA 200 mg Twice Daily isTaken With Combined Hormonal ContraceptivesCo-administration of a combined oral contraceptive (COC) (containing 20 mcg ethinyl estradiol/0.1 mg levonorgestrel) following administration of ORILISSA 200 mg twice daily for 14 days increases the plasma ethinyl estradiol concentration by 2.2-fold compared to this COC alone. ORILISSA 200 mg twice daily co-administered with a COC containing ethinyl estradiol may lead to increased risk of ethinyl estradiol-related adverse events including thromboembolic disorders and vascular events and is not recommended
[see Drug Interactions (7.1), Clinical Pharmacology (12.3)].Potential for Reduced Efficacy ofProgestin-Containing Hormonal ContraceptivesCo-administration of ORILISSA 200 mg twice daily and a COC containing 0.1 mg levonorgestrel decreases the plasma concentrations of levonorgestrel by 27%, potentially affecting contraceptive efficacy. Co-administration of ORILISSA with COCs containing norethindrone acetate did not show reduction in plasma concentrations of norethindrone
[see Drug Interactions (7.1), Clinical Pharmacology (12.3)].Co-administration of ORILISSA with progestin-containing intrauterine contraceptive systems has not been studied.
Reduced efficacy of ORILISSABased 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.