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WARNING: THROMBOEMBOLIC DISORDERS AND VASCULAR EVENTS Estrogen and progestin combinations, including ORIAHNN, increase the risk of thrombotic or thromboembolic disorders including pulmonary embolism, deep vein thrombosis, stroke and myocardial infarction, especially in women at increased risk for these events [see Warnings and Precautions ( 5.1 )] . ORIAHNN is contraindicated in women with current or a history of thrombotic or thromboembolic disorders and in women at increased risk for these events, including women over 35 years of age who smoke and women with uncontrolled hypertension [see Contraindications ( 4 )] . WARNING: THROMBOEMBOLIC DISORDERS AND VASCULAR EVENTS See full prescribing information for complete boxed warning. Estrogen and progestin combinations, including ORIAHNN, increase the risk of thrombotic or thromboembolic disorders, especially in women at increased risk for these events. ( 5.1 ) ORIAHNN is contraindicated in women with current or a history of thrombotic or thromboembolic disorders and in women at increased risk for these events including women over 35 years of age who smoke or women with uncontrolled hypertension. ( 4 )

Risk first

Contraindications

4 CONTRAINDICATIONS ORIAHNN is contraindicated in women: With a high risk of arterial, venous thrombotic, or thromboembolic disorders [see Boxed Warning and Warnings and Precautions ( 5.1 ) ] .
Examples include women over 35 years of age who smoke, and women who are known to have: ○ current or history of deep vein thrombosis or pulmonary embolism ○ vascular disease (e.g., cerebrovascular disease, coronary artery disease, peripheral vascular disease) ○ thrombogenic valvular or thrombogenic rhythm diseases of the heart (for example, subacute bacterial endocarditis with valvular disease, or atrial fibrillation) ○ inherited or acquired hypercoagulopathies ○ uncontrolled hypertension ○ headaches with focal neurological symptoms or have migraine headaches with aura if over age 35 Who are pregnant.
Exposure to ORIAHNN early in pregnancy may increase the risk of early pregnancy loss [see Use in Specific Populations ( 8.1 ) ] .
With known osteoporosis because of the risk of further bone loss [see Warnings and Precautions ( 5.2 ) ] .
With current or history of breast cancer or other hormonally-sensitive malignancies, and with increased risk for hormonally-sensitive malignancies [see Warnings and Precautions ( 5.3 ) ] .
With known hepatic impairment or disease [see Warnings and Precautions ( 5.5 ) ] .
With undiagnosed abnormal uterine bleeding.
With known anaphylactic reaction, angioedema, or hypersensitivity to ORIAHNN or any of its components.
Taking inhibitors of organic anion transporting polypeptide (OATP)1B1 (a hepatic uptake transporter) that are known or expected to significantly increase elagolix plasma concentrations [see Drug Interactions ( 7.2 ) ] .
High risk of arterial, venous thrombotic, or thromboembolic disorder.
( 4 ) Pregnancy.
( 4 ) Known osteoporosis.

Precautions

Events: Discontinue ORIAHNN if an arterial or venous thrombotic, cardiovascular, or cerebrovascular event occurs.
Stop ORIAHNN if there is sudden unexplained partial or complete loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions and evaluate for retinal vein thrombosis immediately.
( 5.1 ) Bone Loss: Duration-dependent decreases in bone mineral density (BMD) that may not be completely reversible.
Baseline and periodic BMD assessments are recommended.
Assess risk-benefit for women with additional risk factors for bone loss.
( 5.2 ) 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.
( 5.4 ) Hepatic Impairment and Transaminase Elevations: Counsel patients on signs and symptoms of liver injury.
( 5.5 ) Elevated Blood Pressure: Do not use in women with uncontrolled hypertension.
For women with well-controlled hypertension, continue to monitor blood pressure and stop ORIAHNN if blood pressure rises significantly.
( 5.6 ) Change in Menstrual Bleeding Pattern and Reduced Ability to Recognize Pregnancy: Advise women to use non-hormonal contraception during treatment and for 28 days after discontinuing ORIAHNN.
ORIAHNN may delay the ability to recognize the occurrence of a pregnancy because it alters menstrual bleeding.
Perform pregnancy testing if pregnancy is suspected and discontinue ORIAHNN if pregnancy is confirmed.

Point of care

Dosing

Adult

(elagolix 300 mg, estradiol 1 mg, norethindrone acetate 0.5 mg) in the morning and one capsule (elagolix 300 mg) in the evening for up to 24 months. ( 2.1 ) 2.1 Important Dosing Information Exclude pregnancy before starting ORIAHNN or start ORIAHNN within 7 days from the onset of menses [see Use in Specific Populations ( 8.1 ) and ( 8.3 ) ] . The recommended dosage of ORIAHNN is: ○ One elagolix 300 mg, estradiol 1 mg, and norethindrone acetate 0.5 mg capsule in the morning (AM), and ○ One elagolix 300 mg capsule in the evening (PM). Take the morning and evening capsules at approximately the same time each day, with or without food. The recommended duration of treatment with ORIAHNN is 24 months [see Warnings and Precautions ( 5.2 ) ] . 2.2 Missed Dose Instruct the patient to take the missed dose of ORIAHNN within 4 hours of the time that it was supposed to be taken and then the next dose at the usual time. If more than 4 hours have passed since a capsule is usually taken, instruct the patient not to take the missed dose and take the next dose at the usual time. Take only one morning capsule and one evening capsule per day.

Paediatric

8.4 Pediatric Use Safety and effectiveness of ORIAHNN in pediatric patients have not been established.

Renal

Review renal impairment dosing; many agents need CrCl/eGFR adjustment.

CrCl 0–120: Confirm renal dosing in product SmPC / primary label.

Hepatic

Review hepatic impairment dosing; monitor LFTs if agent is hepatically cleared or hepatotoxic.

Safety

Drug interactions

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Professional use: confirm indication, dose, duration, monitoring and patient counselling points against current Kenya STG / EML and the product SmPC.
Document allergy status and key interactions.

Safety

Adverse effects

labeling: Thromboembolic Disorders and Vascular Events [see Warnings and Precautions ( 5.1 ) ] Bone Loss [see Warnings and Precautions ( 5.2 ) ] Suicidal Ideation, Suicidal Behavior, and Exacerbation of Mood Disorders [see Warnings and Precautions ( 5.4 ) ] Hepatic Transaminase Elevations [see Warnings and Precautions ( 5.5 ) ] Elevated Blood Pressure [see Warnings and Precautions ( 5.6 ) ] Effects on Carbohydrate and Lipid Metabolism [see Warnings and Precautions ( 5.9 ) ] Alopecia [see Warnings and Precautions ( 5.10 ) ] Most common adverse reaction (>5%) in clinical trials were hot flushes, headache, fatigue, metrorrhagia.
( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact AbbVie Inc. at 1–800–633–9110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch Figure 1.
Mean Percent Change From Baseline in Lumbar Spine BMD in Women Who Received 12 Months of ORIAHNN (On-Treatment) and 12 Months of Follow Up (Off Treatment) 6.1 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 ORIAHNN was evaluated in two 6-month, randomized, double-blind, placebo-controlled trials (Studies UF-1 and UF-2), in which 790 premenopausal women received at least 1 dose of ORIAHNN (n=395), elagolix 300 mg twice daily (n=199), or placebo (n=196) [see Clinical Studies ( 14 )] .
Women who completed 6-month treatment in either Study UF-1 or Study UF-2 and met eligibility criteria (n=433) entered a 6-month extension study (Study UF-3), receiving either ORIAHNN (n=276) or elagolix 300 mg twice daily (n=157).
Elagolix 300 mg twice daily is not an approved dosage but was included as a reference arm.
A total of 341 women received ORIAHNN for 6 months and 182 women received ORIAHNN for 12 months.
Serious Adverse Events Serious adverse events were reported in three (0.8%) ORIAHNN-treated women in Studies UF-1 and UF-2.
Two women had heavy menstrual bleeding and required blood transfusion due to anemia (0.5%) and one woman with history of bariatric surgery had a laparoscopic cholecystectomy due to cholelithiasis.
In Study UF-3, two women were diagnosed with breast cancer.
One woman had completed 6 months of treatment with ORIAHNN in Study UF-1 and received 34 additional days of ORIAHNN in Study UF-3 when diagnosed.
The second woman had received placebo in Study UF-2 and completed 6 months of ORIAHNN in Study UF-3 when diagnosed [see Warnings and Precautions ( 5.3 ) ] .
Adverse Reactions Leading to Study Discontinuation In Studies UF-1 and UF-2, the discontinuation rate due to adverse reactions was 10% among ORIAHNN-treated women and 7% among placebo-treated women.
The most common adverse reactions leading to study drug discontinuation in the ORIAHNN group were nausea (1%), headache (1%), alopecia (1%), metrorrhagia (1%), menorrhagia (1%), and hot flush (1%).

Use

Indications

(fibroids) in premenopausal women.
Limitation of Use: Use of ORIAHNN should be limited to 24 months due to the risk of continued bone loss, which may not be reversible [see Dosage and Administration ( 2.1 ) and Warnings and Precautions ( 5.2 ) ] .
ORIAHNN is a combination of elagolix, a gonadotropin-releasing hormone (GnRH) receptor antagonist, estradiol, an estrogen, and norethindrone acetate, a progestin, indicated for the management of heavy menstrual bleeding associated with uterine leiomyomas (fibroids) in premenopausal women.
( 1 ) Limitation of Use: Use of ORIAHNN should be limited to 24 months due to the risk of continued bone loss, which may not be reversible.

Pharmacology

Mode of action

12.

1 Mechanism of Action ORIAHNN combines ela… → Elagolix is a GnRH receptor antagonist tha… → Administration of elagolix results in dose…

Full mechanism text

12.1 Mechanism of Action ORIAHNN combines elagolix and estradiol/norethindrone acetate (E2/NETA), a combination of estrogen and progestin. Elagolix is a GnRH receptor antagonist that inhibits endogenous GnRH signaling by binding competitively to GnRH receptors in the pituitary gland. Administration of elagolix results in dose-dependent suppression of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), leading to decreased blood concentrations of the ovarian sex hormones estradiol and progesterone and reduces bleeding associated with uterine fibroids. E2 acts by binding to nuclear receptors that are expressed in estrogen-responsive tissues. As a component of ORIAHNN, the addition of exogenous estradiol may reduce the increase in bone resorption and resultant bone loss that can occur due to a decrease in circulating estrogen from elagolix alone. Progestins such as NETA act by binding to nuclear receptors that are expressed in progesterone-responsive tissues. As a component of ORIAHNN, NETA may protect the uterus from the potential adverse endometrial effects of unopposed estrogen.

ADME

Pharmacokinetics & PD

Onset	Product-specific
Duration	Product-specific
Route	See product SmPC
Absorption	Elagolix Estradiol a Norethindrone T max (h) b,c 1.5 (1.0 – 4.0) 2.0 (0.0 - 10.0) 1.0 (0.5 - 2.0) Effect of Food High-fat meal d (relative to fasting) AUC: ↓25%, C max : ↓36% AUC: no change, C max : ↓23% AUC: ↑23%, C max : ↓50%
Distribution	% Bound to human plasma proteins 80 98 97 Blood-to-plasma ratio 0.6 NA NA
Metabolism	Metabolism CYP3A (major) Minor pathways include: CYP2D6, CYP2C8, and uridine glucuronosyl transferases (UGTs) CYP3A (partial) Other pathways include: sulfation and glucuronidation CYP3A (partial)
Elimination	Major route of elimination Hepatic
Half-life	(t 1/2 ) (h) c, e 5.9 ± 2.1 14.5 ± 6.6 9.2 ± 4.0 % of dose excreted in urine <3 NA NA % of dose excreted in feces 90 NA NA NA=not available a Baseline adjusted unconjugated estradiol b Median and range c Following administration of a single dose under fasting conditions d High-fa...

Full PK/PD text

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action ORIAHNN combines elagolix and estradiol/norethindrone acetate (E2/NETA), a combination of estrogen and progestin. Elagolix is a GnRH receptor antagonist that inhibits endogenous GnRH signaling by binding competitively to GnRH receptors in the pituitary gland. Administration of elagolix results in dose-dependent suppression of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), leading to decreased blood concentrations of the ovarian sex hormones estradiol and progesterone and reduces bleeding associated with uterine fibroids. E2 acts by binding to nuclear receptors that are expressed in estrogen-responsive tissues. As a component of ORIAHNN, the addition of exogenous estradiol may reduce the increase in bone resorption and resultant bone loss that can occur due to a decrease in circulating estrogen from elagolix alone. Progestins such as NETA act by binding to nuclear receptors that are expressed in progesterone-responsive tissues. As a component of ORIAHNN, NETA may protect the uterus from the potential adverse endometrial effects of unopposed estrogen. 12.2 Pharmacodynamics Estradiol and norethindrone acetate (components of ORIAHNN) may have the following effects: Increased thyroxin-binding globulin levels leading to [see Warnings and Precautions ( 5.11 ) ]: ○ Increased circulating total thyroid hormone levels as measured by protein-bound iodine (PBI), thyroxine (T4) levels (by column or by radioimmunoassay), or triiodothyronine (T3) levels by radioimmunoassay ○ Decreased T3 resin uptake ○ Unaltered free T4 and free T3 concentrations in women with normal thyroid function [see Warnings and Precautions ( 5.11 ) ] . Elevated corticosteroid-binding globulin (CBG) and sex hormone-binding globulin (SHBG) leading to increased total circulating corticosteroids and sex steroids, respectively [see Warnings and Precautions ( 5.11 ) ] . Possible decreased free testosterone concentrations. Possible increased other plasma proteins concentrations (angiotensinogen/renin substrate, alpha-1 antitrypsin, ceruloplasmin). Increased plasma high-density lipoprotein (HDL) and HDL2 cholesterol subfraction concentration, reduced low-density lipoprotein concentration, increased triglyceride levels [see Warnings and Precautions ( 5.9 ) ] . Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased platelet count; increased factors II, VII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, and beta-thromboglobulin; decreased levels of anti-factor Xa and antithrombin III, decreased antithrombin III activity, increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity. Cardiac Electrophysiology The effect of elagolix (a component of ORIAHNN) on the QTc interval was evaluated in a randomized, placebo- and positive-controlled, open-label, single-dose, crossover thorough QTc study in 48 healthy adult premenopausal women. Elagolix concentrations in women given a single dose of 1200 mg were 9 times higher than the concentration in women given elagolix 300 mg twice daily. There was no clinically relevant prolongation of the QTc interval. The effect of estradiol and norethindrone acetate (two components of ORIAHNN) on the QTc interval has not been studied. 12.3 Pharmacokinetics The pharmacokinetic properties of ORIAHNN in healthy subjects are summarized in Table 4. The pharmacokinetic parameters under fasting conditions are summarized in Table 5. Table 4. Pharmacokinetic Properties of ORIAHNN in Healthy Subjects Absorption Elagolix Estradiol a Norethindrone T max (h) b,c 1.5 (1.0 – 4.0) 2.0 (0.0 - 10.0) 1.0 (0.5 - 2.0) Effect of Food High-fat meal d (relative to fasting) AUC: ↓25%, C max : ↓36% AUC: no change, C max : ↓23% AUC: ↑23%, C max : ↓50% Distribution % Bound to human plasma proteins 80 98 97 Blood-to-plasma ratio 0.6 NA NA Metabolism Metabolism CYP3A (major) Minor pathways include: CYP2D6, CYP2C8, and uridine glucuronosyl transferases (UGTs) CYP3A (partial) Other pathways include: sulfation and glucuronidation CYP3A (partial) Elimination Major route of elimination Hepatic metabolism Hepatic metabolism Hepatic metabolism Terminal phase elimination half-life (t 1/2 ) (h) c, e 5.9 ± 2.1 14.5 ± 6.6 9.2 ± 4.0 % of dose excreted in urine <3 NA NA % of dose excreted in feces 90 NA NA NA=not available a Baseline adjusted unconjugated estradiol b Median and range c Following administration of a single dose under fasting conditions d High-fat meal is approximately 826 kcal, 52% fat. e Mean ± SD Table 5. Mean (%CV) Pharmacokinetic Parameters of ORIAHNN Pharmacokinetic Parameter (Units) Elagolix 300 mg Twice Daily a N = 8 Estradiol b 1 mg N = 163 Norethindrone b 0.5 mg N = 163 C max (ng/mL) 1200 (45) 0.06 (52) 6.1 (35) AUC τ (ng●hr/mL) 2826 (44) 0.86 (38) 23.8 (48) a Data obtained at steady state (Day 21); AUC τ represents the area under the plasma concentration-time curve from 0 to 12 hours post dose. b Data obtained following single dose administration; AUC τ represents AUC from 0 to 24 hours post dose; estradiol: baseline adjusted unconjugated estradiol. CV: Coefficient of variation C max : Plasma peak concentration Specific Populations Patients with Renal Impairment Elagolix exposures (C max and AUC) were not altered by renal impairment. The elagolix mean plasma exposures were similar for women with moderate to severe or end-stage renal disease (including women on dialysis) compared to women with normal renal function. The effect of renal impairment on the pharmacokinetics of E2/NETA has not been studied. Patients with Hepatic Impairment Elagolix exposures (C max and AUC) were similar between women with normal hepatic function and women with mild hepatic impairment. Elagolix exposures in women with moderate and severe hepatic impairment were approximately 3-fold and 7-fold, respectively, higher than exposures from women with normal hepatic function. The use of estradiol in patients with hepatic impairment, compared to patients with normal hepatic function, is expected to increase the estradiol blood levels [see Warnings and Precautions ( 5.5 ) and Use in Specific Populations ( 8.7 ) ] . Racial or Ethnic Groups No clinically meaningful difference in the pharmacokinetics of elagolix between White and Black subjects or between Hispanics and others was observed. There is no clinically meaningful difference in the pharmacokinetics of elagolix between Japanese and Han Chinese subjects. The effect of race/ethnicity on the pharmacokinetics of E2/NETA has not been studied. Body Weight/Body Mass Index Body weight or body mass index does not affect the pharmacokinetics of elagolix. The effect of body weight/body mass index on the pharmacokinetics of E2/NETA has not been studied. Drug Interaction Studies Drug interaction studies were performed with elagolix and other drugs likely to be co-administered and with drugs commonly used as probes for pharmacokinetic interactions. Tables 6 and 7 summarize the pharmacokinetic effects when elagolix was co-administered with these drugs. Table 6. Drug Interactions: Change in Pharmacokinetics of Elagolix in the Presence of Co-administered Drugs Co-administered Drug Co-administered Drug Regimen Elagolix Regimen 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 & The elagolix dose in these studies was 0.5 times the approved dose in ORIAHNN (0.25 times the total approved daily dosage of elagolix in ORIAHNN) * ratios for C max and 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 elagolix 300 mg twice daily was co-administered with rosuvastatin (20 mg once daily), sertraline (25 mg once daily), or fluconazole (200 mg single dose). The effect of co-administered rosuvastatin, sertraline, or fluconazole on E2/NETA has not been studied. Table 7. Drug Interactions: Change in Pharmacokinetics of Co-administered Drug in the Presence of Elagolix Co-administered Drug Co-administered Drug Regimen Elagolix Regimen 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) 2 mg single dose 150 mg once daily x 13 days 11 0.81 (0.74 - 0.89) 0.65 (0.58 - 0.72) 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 C max and AUC compare co-administration of the medication with elagolix vs. administration of the medication alone. No clinically significant changes in sertraline, fluconazole, bupropion, or transdermal patch E2/NETA 0.51/4.8 mg exposures were observed when co-administered with elagolix 300 mg twice daily. 12.5 Pharmacogenomics Hepatic uptake of elagolix (a component of ORIAHNN) involves the OATP1B1 transporter protein. Higher plasma concentrations of elagolix have been observed in patients who have two reduced function alleles of the gene that encodes OATP1B1 (SLCO1B1 521T>C) (these patients are likely to have reduced hepatic uptake of elagolix and thus, higher plasma elagolix concentrations). The frequency of the SLCO1B1 521C/C genotype is generally less than 5% in most racial/ethnic groups. Women with this genotype are expected to have approximately 2-fold higher elagolix mean concentrations compared to women with normal transporter function (i.e., SLCO1B1 521T/T genotype). Adverse effects of elagolix have not been fully evaluated in subjects who have two reduced function alleles of the gene that encodes OATP1B1 (SLCO1B1 521T>C).

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Special populations

Pregnancy & lactation

Pregnancy

8.1 Pregnancy Risk Summary Use of ORIAHNN is contraindicated in pregnant women. Exposure to elagolix early in pregnancy may increase the risk of early pregnancy loss. Discontinue ORIAHNN if pregnancy occurs during treatment. The limited human data with the use of elagolix in pregnant women are insufficient to determine whether there is a risk for major birth defects or miscarriage [see Data ]. When pregnant rats and rabbits were orally dosed with elagolix during the period of organogenesis, postimplantation loss was observed in pregnant rats at doses 12 times the maximum recommended human dose (MRHD). Spontaneous abortion and total litter loss were observed in rabbits at doses 4 and 7 times the MRHD. There were no structural abnormalities in the fetuses at exposures up to 25 and 7 times the MRHD for the rat and rabbit, respectively [see Data ] . Data Human Data There was one pregnancy reported in the 453 women who received ORIAHNN in the Phase 3 uterine fibroids clinical trials. The pregnancy resulted in a spontaneous abortion and the estimated fetal exposure to ORIAHNN occurred during the first 18 days of pregnancy. Animal Data 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 12 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 7 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 4 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 25 and 7 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 0.04-fold and 0.1-fold the maximal elagolix concentration (C max ) 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.

Lactation

8.1 Pregnancy Risk Summary Use of ORIAHNN is contraindicated in pregnant women. Exposure to elagolix early in pregnancy may increase the risk of early pregnancy loss. Discontinue ORIAHNN if pregnancy occurs during treatment. The limited human data with the use of elagolix in pregnant women are insufficient to determine whether there is a risk for major birth defects or miscarriage [see Data ]. When pregnant rats and rabbits were orally dosed with elagolix during the period of organogenesis, postimplantation loss was observed in pregnant rats at doses 12 times the maximum recommended human dose (MRHD). Spontaneous abortion and total litter loss were observed in rabbits at doses 4 and 7 times the MRHD. There were no structural abnormalities in the fetuses at exposures up to 25 and 7 times the MRHD for the rat and rabbit, respectively [see Data ] . Data Human Data There was one pregnancy reported in the 453 women who received ORIAHNN in the Phase 3 uterine fibroids clinical trials. The pregnancy resulted in a spontaneous abortion and the estimated fetal exposure to ORIAHNN occurred during the first 18 days of pregnancy. Animal Data 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 12 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 7 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 4 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 25 and 7 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 0.04-fold and 0.1-fold the maximal elagolix concentration (C max ) 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. 8.2 Lactation Risk Summary There is no information on the presence of elagolix or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. When estrogen and progestins are administered to lactating women, these compounds and/or their metabolites are detected in human milk and can reduce milk production in breast-feeding females. This reduction can occur at any time but is less likely to occur once breast-feeding is well established. Advise the nursing female to use non-hormonal contraception until she discontinues breast-feeding. The developmental and health benefits of breast-feeding should be considered along with the mother’s clinical need for ORIAHNN and any potential adverse effects on the breast-fed child from ORIAHNN or from the underlying maternal condition [see Data ] . Data There is no information on the presence of elagolix or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. Estrogen administration to nursing women has been shown to decrease the quantity and quality of the breast milk. Detectable amounts of estrogen and progestin have been identified in the breast milk of women receiving estrogen and progestin combinations. There are no adequate animal data on excretion of elagolix in milk. 8.3 Females and Males of Reproductive Potential Based on the mechanism of action of elagolix, there is a risk of early pregnancy loss if ORIAHNN is administered to a pregnant woman [see Use in Specific Populations ( 8.1 ) , Clinical Pharmacology ( 12.1 ) ] . Pregnancy Testing ORIAHNN may delay the ability to recognize the occurrence of a pregnancy because it may reduce the intensity, duration, and amount of menstrual bleeding [see Adverse Reactions ( 6.1 ) ] . Exclude pregnancy before initiating treatment with ORIAHNN. Perform pregnancy testing if pregnancy is suspected during treatment with ORIAHNN and discontinue treatment if pregnancy is confirmed [see Contraindications ( 4 ) and Warnings and Precautions ( 5.8 ) ] . Contraception Advise women to use non-hormonal contraception during treatment with ORIAHNN and for 28 days after discontinuing ORIAHNN [see Warnings and Precautions ( 5.8 ) ] . 8.4 Pediatric Use Safety and effectiveness of ORIAHNN in pediatric patients have not been established. 8.6 Renal Impairment No dose adjustment of ORIAHNN is required in women with any degree of renal impairment or end-stage renal disease (including women on dialysis) [see Clinical Pharmacology ( 12.3 ) ] . 8.7 Hepatic Impairment ORIAHNN is contraindicated in women with any hepatic impairment or disease [see Contraindications ( 4 ) ] . The use of estradiol (a component of ORIAHNN) in patients with hepatic impairment, compared to patients with normal hepatic function, is expected to increase the blood levels of estradiol and increase the risk of estradiol-associated adverse reactions. Additionally, the use of elagolix (a component of ORIAHNN) in patients with moderate and severe hepatic impairment, compared to patients with normal hepatic function, increased elagolix exposures 3-fold and 7-fold, respectively, and this increases the risk of elagolix-associated adverse reactions [see Clinical Pharmacology ( 12.3 ) ] .

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Source: Local active-ingredient clinical extract; FDA drug label via OpenFDA/DailyMed; Professional class pharmacology (Therapeutic agent (verify pharmacological class))

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Norethisterone