Elagolix (Orilissa) is an orally available GnRH ( gonadotropin releasing hormone antagonist) that causes the suppression of estradiol and gonadotropins. It is used to treat the symptoms associated with endometriosis such as moderate to severe pelvic pain and dysmenorrhea.

Elagolix (Orilissa) Uses:

• Endometriosis:

  • It is indicated for the management of pain of moderate to severe intensity associated with endometriosis.

Adult dose:

Note:

• Use the lowest effective dose and for the shortest possible duration to achieve treatment goals and simultaneously limit adverse effects such as bone loss associated with the treatment.

Elagolix (Orilissa) Dose in the treatment of Endometriosis:

• Initial: 150 mg orally once a day.
• The maximum duration of treatment is 24 months

Elagolix (Orilissa) Dose in the treatment of Endometriosis with dyspareunia:

• Treatment should be initiated in a dose of 200 mg orally twice daily
• The maximum duration of treatment is 6 months

• Missed dose:

  • If a dose is missed, it should be administered as soon as remembered. The regular dosage schedule should be then followed.
  • Patients who are on 150 mg or less dose per day should avoid taking more than one tablet per day.
  • Patients who are on 200 mg dose daily should not exceed two tablets per day.

Use in Children:

Not indicated in children. 

Elagolix (Orilissa) Pregnancy Risk Category: X

• Although data regarding its use during oregnancy are limited, the drug's mechanism of action makes it contraindicated during pregnancy.
• It is more likely to cause early pregnancy loss if it is used during pregnancy.
• Before treatment is initiated, you should exclude pregnancy. The drug should be stopped if pregnancy is suspected.
• It does not completely stop ovulation. It is recommended that nonhormonal contraceptives be used throughout the treatment, and at least for one week following the last dose.

Elagolix use during breastfeeding:

• It is unknown if the drug will be excreted into breastmilk.
• Manufacturer suggests weighing the benefits and risks of drug tnerapy for the mother against the potential dangers to the infant.

Elagolix (Orilissa) Dose in Kidney disease:

• Mild, moderate, or severe impairment:
  • Adjustment in the dose is not necessary.
• ESRD:
  • Adjustment in the dose is not necessary.

Elagolix (Orilissa) Dose in Liver disease:

• Mild impairment (Child-Pugh class A):
  • Adjustment in the dose is not necessary.
• Moderate impairment (Child-Pugh class B):
  • Initiate treatment in a dose of150 mg orally once a day for a maximum duration of six months.
  • Avoid using 200 mg twice daily dose in moderate hepatic impairment.
• Severe impairment (Child-Pugh class C):
  • The drug is contraindicated in severe hepatic impairment.

Common Side Effects of Elagolix (Orilissa):

• Central Nervous System:

  • Headache

• Dermatologic:

  • Night Sweats

• Endocrine & Metabolic:

  • Amenorrhea
  • Hot Flash

• Gastrointestinal:

  • Nausea

• Neuromuscular & Skeletal:

  • Decreased Bone Mineral Density

Less Common Side Effects Of Elagolix (Orilissa):

• Central Nervous System:

  • Insomnia
  • Depressed Mood
  • Depression
  • Emotional Lability
  • Lacrimation
  • Mood Changes
  • Anxiety
  • Dizziness
  • Irritability

• Endocrine & Metabolic:

  • Decreased Libido
  • Weight Gain

• Gastrointestinal:

  • Abdominal Pain
  • Constipation
  • Diarrhea

• Hepatic:

  • Increased Serum Alanine Aminotransferase

• Neuromuscular & Skeletal:

  • Arthralgia

Rare Side effects of Elagolix (Orilissa):

• Endocrine & Metabolic:

  • Increased HDL Cholesterol
  • Increased LDL Cholesterol
  • Increased Serum Cholesterol
  • Increased Triglycerides

• Genitourinary:

  • Menstrual flow (reduction in the amount, intensity, or duration of menstrual bleeding)

Contraindications to Elagolix (Orilissa):

• • • Pregnancy
    • Osteoporosis patients
    • Severe hepatic impairment (Child Puugh class C).
    • Use of OATP 1B1 inhibitors (cyclosporine, gemfibrozil) in conjunction with strong organic anion transporting peptides (OATP).

Canadian labeling: Additional contraindications not in US labeling

• • • Hypersensitivity to any drug or component of the formulation
    • Vaginal bleeding that is not diagnosed

Warnings and precautions

• • Bleeding irregularities:

    • The drug reduces the severity, duration, or amount of bleeding. This could make it difficult to notice pregnancy.
    • It is important to have a pregnancy test done before starting treatment and during treatment.
    • If pregnancy is confirmed, treatment must be stopped.

  • BMD loss:

    • Treatment may cause a loss of bone mineral density.
    • As the duration of treatment is extended, the risk increases and may not be reversed (on discontinuation).
    • Assess the risk factors of osteoporosis before treatment begins, including any history of fractures after minor trauma.
    • Consider supplementing with vitamin D and calcium.
    • To prevent bone loss, the treatment should be stopped for as little time as possible.
    • People with osteoporosis are advised to avoid this drug.

  • Depression

    • Treatment with elagolix can cause mood disturbances such as major depression and suicidal thoughts.
    • Patients with a history of depression are at greater risk of experiencing mental changes.
    • Patients with new symptoms of psychiatric disorders should be evaluated immediately and referred to a psychiatrist.
    • If you are concerned about depression or suicidal thoughts, it is worth considering discontinuing treatment.

  • Hepatic impairment

    • Transaminitis is a condition that can be treated. A dose-dependent increase in ALT levels can occur. To avoid liver toxicity, the minimal effective dose should always be used.
    • Hepatotoxicity in patients should be diagnosed and treated accordingly.
    • If you have severe hepatic impairment, avoid using this drug. Adjust the dose for moderate to severe hepatic impairment.

Elagolix: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

  Risk Factor C (Monitor therapy).
  Aprepitant	High risk of Inhibitors causing an increase in serum CYP3A4 Substrates concentrations
  Brentuximab Vedotin	Brentuximab Vedotin may be increased by P-glycoprotein/ABCB1 inhibitors. Concentrations of the monomethyl auristatin E component (MMAE) may increase.
  Celiprolol	The serum concentration of Celiprolol may be increased by P-glycoprotein/ABCB1 inhibitors
  Clofazimine	High risk of Inhibitors causing an increase in serum CYP3A4 Substrates concentrations
  CloZAPine	CloZAPine serum concentrations may be decreased by CYP3A4 Inducers (Weak).
  Strong CYP3A4 Inducers	Might decrease the serum Elagolix concentration.
  Moderate CYP3A4 inhibitors	Might decrease metabolism of CYP3A4 substrates (High Risk with Inhibitors).
  Digoxin	The serum Digoxin concentration may be increased by Elagolix.
  Duvelisib	High risk of Inhibitors causing an increase in serum CYP3A4 Substrates concentrations
  Erdafitinib	High risk of Inhibitors causing an increase in serum CYP3A4 Substrates concentrations
  Everolimus	Everolimus serum concentration may be increased by P-glycoprotein/ABCB1 inhibitors
  Fosaprepitant	High risk of Inhibitors causing an increase in serum CYP3A4 Substrates concentrations
  Fosnetupitant	High risk of Inhibitors causing an increase in serum CYP3A4 Substrates concentrations
  Larotrectinib	High risk of Inhibitors causing an increase in serum CYP3A4 Substrates concentrations
  Larotrectinib	The serum concentration of Larotrectinib may be increased by P-glycoprotein/ABCB1 inhibitors
  Midazolam	Elagolix could decrease Midazolam's serum concentration.
  Naldemedine	The serum concentrations of Naldemedine may be increased by P-glycoprotein/ABCB1 inhibitors.
  Naloxegol	The serum concentrations of Naloxegol may be increased by P-glycoprotein/ABCB1 inhibitors.
  Netupitant	High risk of Inhibitors causing an increase in serum CYP3A4 Substrates concentrations
  NiMODipine	CYP3A4 Inducers, (Weak), may reduce the serum NiMODipine concentration.
  Palbociclib	High risk of Inhibitors causing an increase in serum CYP3A4 Substrates concentrations
  P-glycoprotein/ABCB1 Substrates	P-glycoprotein/ABCB1 inhibitors may increase serum levels of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors can also increase the distribution of p.glycoprotein substrates in specific cells/tissues/organs that have high levels (e.g. brain, T-lymphocytes and testes). Loperamide is an exception.
  Prucalopride	The serum concentrations of Prucalopride may be increased by P-glycoprotein/ABCB1 inhibitors.
  Ranolazine	Ranolazine may be increased by P-glycoprotein/ABCB1 inhibitors.
  RifAXIMin	The serum concentrations of RifAXIMin may be increased by P-glycoprotein/ABCB1 inhibitors
  Rosuvastatin	Rosuvastatin serum concentrations may be decreased by Elagolix.
  Silodosin	The serum concentrations of Silodosin may be increased by P-glycoprotein/ABCB1 inhibitors.
  Talazoparib	Talazoparib serum concentration may be increased by P-glycoprotein/ABCB1 inhibitors. Management: The following exceptions are addressed in separate interaction monographs.
  Risk Factor D (Consider therapy modifications)
  Afatinib	The serum concentrations of Afatinib may be increased by P-glycoprotein/ABCB1 inhibitors. If afatinib is not tolerated, reduce the dose by 10 mg. Canadian labeling states that it is best to avoid combination therapy. If you must use the P-gp inhibitor, do so simultaneously with or after afatinib.
  Betrixaban	The serum concentration of Betrixaban may be increased by P-glycoprotein/ABCB1 inhibitors. Management: Reduce the initial dose of betrixaban to 80 mg, followed by 40 mg daily if taken with a Pglycoprotein inhibitor.
  Bilastine	Bilastine may be increased by P-glycoprotein/ABCB1 inhibitors. Patients with severe or moderate renal impairment who are on p-glycoprotein inhibitors should consider other options.
  Colchicine	The serum Colchicine concentration may be increased by P-glycoprotein/ABCB1 inhibitors. The distribution of Colchicine into specific tissues, such as the brain, may be increased. Patients with impaired renal and hepatic function, who are also taking a p–glycoprotein inhibitor, should not be given colchicine. Reduce the dose of colchicine for those with normal renal or hepatic function. See full monograph for details.
  Strong CYP3A4 inhibitors	Could increase serum Elagolix concentrations. Management: Do not use the elagolix 200mg twice daily with a strong CYP3A4 inhibitor for more than 1 month. The combined use of the elagolix 150m once daily with a strong CYP3A4 inhibitor should be limited to a maximum period of six months.
  Dabigatran Etexilate	The serum concentrations may be increased by P-glycoprotein/ABCB1 inhibitors. Treatment: Dabigatran dosage reductions may be necessary. Particular recommendations can vary depending on the labeling of the US and Canada, the specific P-gp inhibitor, renal function, indications for dabigatran, and other factors. Refer to the full monograph and dabigatran labeling.
  DOXOrubicin (Conventional)	P-glycoprotein/ABCB1 inhibitors may increase serum levels of DOXOrubicin (Conventional). Treatment: If you are treated with doxorubicin, consider alternative P-glycoprotein inhibitors. These combinations should be avoided according to one U.S. manufacturer, Pfizer Inc.
  Edoxaban	The serum concentrations of Edoxaban may be increased by P-glycoprotein/ABCB1 inhibitors. Management: See full monograph for details. Patients receiving edoxaban to treat venous embolism are advised to take lower doses when taking it with P-gp inhibitors. For patients with atrial fibrillation, edoxaban should not be adjusted in the same way.
  Estrogen Derivatives (Contraceptive)	Elagolix may have a less therapeutic effect. Treatment: Continue treatment with Elagolix for at least one week.
  MiFEPRIStone	High risk of Inhibitors causing an increase in serum concentrations of CYP3A4 substrates. Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid dihydroergotamine and ergotamine.
  RifAMPin	Could increase serum Elagolix concentrations. Management: Avoid taking the elagolix 200mg twice daily with rifampin. The combined use of the elagolix 150m once daily dose with Rifampin should be limited to 6 months.
  Stiripentol	High risk of Inhibitors causing an increase in serum concentrations of CYP3A4 substrates. Management: Avoid stiripentol use with CYP3A4 Substrates that have a narrow therapeutic Index. This is to avoid adverse effects and toxicities. Monitoring of any CYP3A4 substrate that is used with stiripentol should be closely done.
  Tolvaptan	May increase serum OATP1B1/1B3 (SLCO1B1/1B3) Substrates.
  Venetoclax	Venetoclax may be increased by P-glycoprotein/ABCB1 inhibitors. Treatment: Patients who are concomitantly treated with P-glycoprotein inhibitors (P-gp), should consider a venetoclax dose decrease of at least 50%.
  Risk Factor X (Avoid Combination)
  Conivaptan	High risk of Inhibitors causing an increase in serum CYP3A4 Substrates concentrations
  Fusidic Acid (Systemic).	High risk of Inhibitors causing an increase in serum CYP3A4 Substrates concentrations
  Idelalisib	High risk of Inhibitors causing an increase in serum CYP3A4 Substrates concentrations
  OATP1B1/1B3 Inhibitors (SLCO1B1/1B3)	Might increase serum Elagolix concentrations.
  PAZOPanib	P-glycoprotein/ABCB1 inhibitors may increase serum levels of PAZOPanib.
  Topotecan	Topotecan serum concentrations may be increased by P-glycoprotein/ABCB1 inhibitors
  VinCRIStine (Liposomal)	The serum VinCRIStine (Liposomal) concentration may be increased by P-glycoprotein/ABCB1 inhibitors

Monitoring parameters:

• Pregnancy test before treatment initiation and during treatment if clinically indicated.
• Liver function tests
• Bone mineral density (consider BMD after 12 months of the treatment).
• Monitor the patient for signs and symptoms of depression and suicidal ideation.

How to administer Elagolix (Orilissa)?

It is administered orally at the same time of the day each day with or without food. Treatment must be initiated within seven days of the menstrual cycle (otherwise exclude pregnancy before initiating the treatment). 

Mechanism of action of Elagolix (Orilissa):

It is a nonpeptide gonadotropin-releasing hormone (GnRH) antagonist with a brief duration of action. GnRH inhibition results in suppression of pituitary hormones and ovarian hormones (i.e. FSH, LH and estradiol levels are affected by GnRH inhibition. Dose-dependent effects are possible.

After treatment has ended, estradiol concentrations return quickly to their baseline levels. Endometriosis symptoms such as dysmenorrhea and non-menstrual pelvic pain can be improved by reducing the levels of estradiol and gonadotropins. Note: BMI does not affect the pharmacokinetics of the drug. Onset of action:

• Suppression of FSH, LH, and estradiol suppression:
  • Within hours of the drug administration on day 1.

Duration:

• After treatment discontinuation, the serum cncentration of FSH, LH, and estradiol return to baseline within 24 to 48 hours.

Absorption:

• Rapid.

Protein binding:

• 80% of the drug is bound to plasma proteins

Metabolism:

• It is metabolized in the liver via CYP3A (major pathway) and CYP2D6, CYP2C8, and UGTs

Half-life elimination:

• 4 to 6 hours

Time to peak:

• 1 hour

Excretion:

• Feces 90%;
• urine <3%

International Brand Names of Elagolix:

• Orilissa

Elagolix Brand Names in Pakistan:

No Brands Available in Pakistan.