DRUG INTERACTIONS-

 1. Potential for ORILISSA to Affect Other Drugs -Elagolix is a weak to moderate inducer of cytochrome P450 (CYP) 3A. Co-administration with ORILISSA may decrease plasma concentrations of drugs that are substrates of CYP3A.

Elagolix is an inhibitor of efflux transporter P-glycoprotein (P-gp).  Co-administration with ORILISSA may increase plasma concentrations of drugs that are substrates of P-gp (e.g., digoxin).

2. Potential for Other Drugs to Affect ORILISSA -                                                           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 drugs that induce CYP3A may decrease elagolix plasma concentrations.

The effect of concomitant use of P-gp inhibitors or inducers on the pharmacokinetics of ORILISSA is unknown.  Co-administration of ORILISSA with drugs that inhibit OATP1B1 may increase elagolix plasma concentrations. Concomitant use of ORILISSA and strong OATP1B1 inhibitors (e.g., cyclosporine and gemfibrozil) is contraindicated         

BRIEF SUMMARY

ELAGOLIX SODIUM (July 2018)

Indn-     For the radical cure (prevention of relapse) of  Plasmodium  malaria       

Comp-   Oral tablets: 150 mg and 200 mg . It is a gonadotropin-releasing hormone (GnRH) receptor antagonist indicated for the management of moderate to severe pain associated with endometrios

ADR-   Most common adverse reactions (>5%) in clinical trials included hot flushes and night sweats, headache, nausea, insomnia, amenorrhea, anxiety, arthralgia, depression-related adverse reactions and mood changes

CI-  • Pregnancy  • Known osteoporosis  • Severe hepatic impairment  • Strong organic anion transporting polypeptide (OATP) 1B1 inhibitors

WARNINGS-                                                                                                                        • 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

Pat Inform-

 • Advise patients on contraceptive options, not to get pregnant while using ORILISSA, to be mindful that menstrual changes could reflect pregnancy and to discontinue ORILISSA if pregnancy occurs 

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U.S. FDA APPROVED  DRUGS DURING 2018

Sr.No-  24

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use

 ORILISSA safely and effectively. See full prescribing information for ORILISSA. ORILISSATM (elagolix) tablets, for oral use

 Initial U.S. Approval: 2018

INDICATIONS AND USAGE

ORILISSA is a gonadotropin-releasing hormone (GnRH) receptor antagonist indicated for the management of moderate to severe pain associated with endometriosis.

DOSAGE AND ADMINISTRATION

Normal liver function or mild hepatic impairment: 150 mg once daily for up to 24 months or 200 mg twice daily for up to 6 months.

 Moderate hepatic impairment: 150 mg once daily for up to 6 months.

DOSAGE FORMS AND STRENGTHS-                                                                               Oral tablets: 150 mg and 200 mg

ADVERSE REACTIONS

Most common adverse reactions (>5%) in clinical trials included hot flushes and night sweats, headache, nausea, insomnia, amenorrhea, anxiety, arthralgia, depression-related adverse reactions and mood changes

CONTRAINDICATIONS

   • Pregnancy                                                                                                                         • Known osteoporosis                                                                                                          • Severe hepatic impairment                                                                                               • Strong organic anion transporting polypeptide (OATP) 1B1 inhibitors

WARNINGS AND PRECAUTIONS-                                                           

 • 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

• 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

 • Suicidal Ideation and Mood Disorders: Advise patients to seek medical attention for suicidal ideation, suicidal behaviour, new onset or worsening depression, anxiety, or other mood changes

• Hepatic Transaminase Elevations: Dose-dependent elevations in serum alanine aminotransferase (ALT). Counsel patients on signs and symptoms of liver injury

• Potential for Reduced Efficacy with Estrogen-Containing Contraceptives: Use non-hormonal contraception during treatment and for one week after discontinuing ORILISSA

INDICATIONS AND USAGE

ORILISSA is a gonadotropin-releasing hormone (GnRH) receptor antagonist indicated for the management of moderate to severe pain associated with endometriosis.

DOSAGE AND ADMINISTRATION

Normal liver function or mild hepatic impairment: 150 mg once daily for up to 24 months or 200 mg twice daily for up to 6 months.

 Moderate hepatic impairment: 150 mg once daily for up to 6 months.

DOSAGE FORMS AND STRENGTHS-                                                                               Oral tablets: 150 mg and 200 mg

 PATIENT COUNSELING INFORMATION

Advise patients to read the FDA-approved patient labelling (Medication Guide).

 • Advise patients on contraceptive options, not to get pregnant while using ORILISSA, to be mindful that menstrual changes could reflect pregnancy and to discontinue ORILISSA if pregnancy occurs 

• Inform patients that estrogen containing contraceptives are expected to reduce the efficacy of ORILISSA.

• Inform patients about the risk of bone loss. Advise adequate intake of calcium and vitamin D

 • Advise patients to seek immediate medical attention for suicidal ideation and behaviour. Instruct patients with new onset or worsening depression, anxiety, or other mood changes to promptly seek medical attention

• Counsel patients on signs and symptoms of liver injury

 • Instruct patients who miss a dose of ORILISSA to take the missed dose on the same day as soon as she remembers and then resume the regular dosing schedule: o 150 mg once daily: no more than 1 tablet each day should be taken. o 200 mg twice daily: no more than 2 tablets each day should be taken.

• Instruct patients to dispose of unused medication via a take-back option if available or to otherwise follow FDA instructions for disposing of medication in the household trash, www.fda.gov/drugdisposal, and not to flush down the toilet.

Manufactured by AbbVie Inc. North Chicago, IL 60064

© 2018 AbbVie Inc. All rights reserved. 03-B517 July 2018

CLINICAL PHARMACOLOGY

 1. Mechanism of Action -                                                                                                   ORILISSA is a GnRH receptor antagonist that inhibits endogenous GnRH signalling by binding competitively to GnRH receptors in the pituitary gland

Administration of ORILISSA 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.

2. Pharmacodynamics -                                                                                                     Effect on Ovulation and Estradiol -                                                                                In a 3-menstrual cycle study in healthy women, ORILISSA 150 mg once daily and 200 mg twice daily resulted in an ovulation rate of approximately 50% and 32%, respectively.

In the Phase 3 trials in women with endometriosis, ORILISSA caused a dose-dependent reduction in median estradiol concentrations to approximately 42 pg/mL for 150 mg once daily regimen and 12 pg/mL for the 200 mg twice daily regimen.

Cardiac Electrophysiology-                                                                                              The effect of elagolix 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 subjects given a single dose of 1200 mg was 17-times higher than the concentration in subjects given elagolix 200 mg twice daily. There was no clinically relevant prolongation of the QTc interval.

3. Pharmacokinetics-                                                                                                    The pharmacokinetic properties of ORILISSA in healthy subjects are summarized below-                                                                                                      Pharmacokinetic Properties of ORILISSA in Healthy Subjects

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

Specific Populations

Renal Impairment -                                                                                                            Elagolix exposures (Cmax and 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.

Hepatic Impairment-                                                                                                          Elagolix exposures (Cmax and 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

Race/Ethnicity -                                                                                                                   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/Body mass index -Body weight or body mass index does not affect the pharmacokinetics of ORILISSA.

 OVERDOSAGE-                                                                                                              In case of overdose, monitor the patient for any signs or symptoms of adverse reactions and initiate appropriate symptomatic treatment, as needed.

  USE IN SPECIFIC POPULATIONS

1. Pregnancy                                                                                                                        Risk Summary -                                                                                                              Exposure to ORILISSA early in pregnancy may increase the risk of early pregnancy loss. Use of ORILISSA is contraindicated in pregnant women.  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. The background risk for major birth defects and miscarriage in the indicated population are unknown.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.            

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.   

There are no adequate on excretion of ORILISSA in milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ORILISSA and any potential adverse effects on the breastfed child from ORILISSA.

3. Females and Males of Reproductive Potential-                                                           Based on the mechanism of action, there is a risk of early pregnancy loss if ORILISSA is administered to a pregnant woman.

Pregnancy Testing-                                                                                                             Exclude pregnancy before initiating treatment with ORILISSA.  Perform pregnancy testing if pregnancy is suspected during treatment with ORILISSA.

Contraception -Advise women to use effective non-hormonal contraception during treatment with ORILISSA and for one week after discontinuing ORILISSA.

4. Pediatric Use -                                                                                                                  Safety and effectiveness of ORILISSA in patients less than 18 years of age have not been established.

5.Renal Impairment -                                                                                                           No dose adjustment of ORILISSA is required in women with any degree of renal impairment or end-stage renal disease (including women on dialysis)

6. 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.

.