DRUGS IN CLASS

MECHANISM OF ACTION

Elinzanetant is a neurokinin 1 (NK1) and neurokinin 3 (NK3) receptor antagonist. Inhibition of Substance P and Neurokinin B through antagonism of NK1 and NK3 receptor signaling on kisspeptin/neurokinin B/dynorphin (KNDy) neurons can modulate neuronal activity in thermoregulation associated with hot flashes.
Elinzanetant has higher affinity for human NK1 receptors (pKi values of 8.7 to 10.2) and NK3 receptors (pKi values of 8.0 to 8.8) than for human NK2 receptors (pKi values of approximately 6.0). [1]

FDA-APPROVED INDICATIONS

Elinzanetant is indicated for the treatment of moderate to severe vasomotor symptoms (VMS) due to menopause. [1]

MENOPAUSAL SYMPTOMS

Co-primary endpoints: mean change in VMS frequency and severity from baseline to Weeks 4 and 12

LS-Mean - Least-square mean

P<0.0001 for all primary comparisons vs. placebo.

Reference [1]
Elinzanetant Effects on Moderate to Severe VMS Over 4 and 12 Weeks
	OASIS 1		OASIS 2
Parameter	Lynkuet 120 mg (N=199)	Placebo (N=197)	Lynkuet 120 mg (N=200)	Placebo (N=200)
Mean Change in Daily Frequency of Moderate to Severe VMS
Baseline (Mean)	13.38	14.26	14.66	16.16
LS-Mean Change at 4 Weeks	-7.60	-4.31	-8.58	-5.54
LS-Mean Change at 12 Weeks	-8.66	-5.44	-9.72	-6.48
Mean Change in Daily Severity of Moderate to Severe VMS
Baseline (Mean)	2.56	2.33	2.53	2.54
LS-Mean Change at 4 Weeks	-0.73	-0.40	-0.75	-0.53
LS-Mean Change at 12 Weeks	-0.92	-0.52	-0.91	-0.62

In the trials above, Elinzanetant reduced VMS frequency by approximately 3 episodes per day (baseline average 14.6) compared to placebo. The severity of symptoms was also significantly reduced.

SIDE EFFECTS

Adverse reactions reported in ≥ 2% of women and more commonly than placebo over 52 weeks
Common Adverse Reactions
Side effect	Elinzanetant 120 mg (N=313)	Placebo (N=314)
Headache	9.6%	7.0%
Fatigue (includes asthenia)	7.3%	2.9%
Dizziness (includes vertigo/presyncope)	6.1%	1.9%
Somnolence (includes lethargy)	5.1%	1.3%
Abdominal pain (includes upper/lower discomfort)	4.5%	2.5%
Rash (includes dermatitis, urticaria)	4.2%	1.6%
Diarrhea	3.8%	1.0%
Muscle spasms (includes muscle tightness)	3.2%	0.6%

Nervous system effects (including somnolence, fatigue, vertigo, dizziness, and presyncope) occurred in 11.9% of patients on Elinzanetant compared to 3.5% on placebo in the OASIS trials. Advise patients who experience these effects to refrain from driving or engaging in hazardous occupations or activities until the effects have resolved. [1]

Elevations in serum transaminase (ALT and/or AST) ≥ 3 X ULN occurred in 0.6% of patients receiving Elinzanetant and 0.4% of women receiving placebo up to 12 weeks.
Before therapy: Perform baseline hepatic laboratory tests (ALT, AST, ALP, and serum bilirubin total/direct) prior to Elinzanetant initiation. Do not start Elinzanetant if ALT or AST is ≥ 2 X ULN or if the total bilirubin is ≥ 2 X ULN.
During therapy: Perform follow-up evaluations of hepatic transaminase concentration 3 months after initiation of therapy. Advise patients to discontinue Elinzanetant immediately and seek medical attention if they experience signs/symptoms that may suggest liver injury (e.g., new onset fatigue, decreased appetite, nausea, vomiting, pruritus, jaundice, pale feces, dark urine, or abdominal pain).
Abnormal liver tests: Discontinue Elinzanetant if transaminase elevations are > 5 X ULN or if transaminase elevations are > 3 X ULN and total bilirubin is > 2 X ULN. Exclude alternative causes of hepatic laboratory test elevations.

CONTRAINDICATIONS

PRECAUTIONS

Elinzanetant is contraindicated in pregnancy. Exclude pregnancy in females of reproductive potential prior to initiating Elinzanetant. Advise females of reproductive potential to use effective contraception during treatment with Elinzanetant and for 2 weeks after stopping Elinzanetant. [1]

Seizure was reported in one patient with a history of seizures in clinical trials. Convulsions were also observed in animal studies. Use Elinzanetant with caution in patients with a history of seizures or with conditions that potentially lower the seizure threshold. [1]

eGFR 15 - 90 mL/min (Mild to Severe Impairment): No dose adjustment is required.
eGFR < 15 mL/min with or without hemodialysis: NOT RECOMMENDED. [1]

DRUG INTERACTIONS

NOTE: The drug interactions presented here are NOT all-inclusive. Other interactions may exist. Drug interaction checkers provide the most efficient and practical way to check for interactions among multiple medications. A free interaction checker is available from Drugs.com (see Drugs.com interactions checker).

Strong CYP3A4 Inhibitors and Grapefruit (juice): AVOID CONCOMITANT USE. Elinzanetant exposure is significantly increased (AUC increase 6.3-fold).
Moderate CYP3A4 Inhibitors: REDUCE ELINZANETANT DOSAGE TO 60 mg once daily. After discontinuation of the inhibitor, return Elinzanetant to 120 mg once daily.
Strong and Moderate CYP3A4 Inducers: AVOID CONCOMITANT USE. Elinzanetant exposure is decreased, which may reduce effectiveness.
Sensitive CYP3A4 Substrates: AVOID CONCOMITANT USE unless otherwise recommended, as Elinzanetant is a weak inhibitor of CYP3A4 and increases exposure of these substrates (e.g., midazolam AUC increase 1.8-fold). [1]

DOSING

Recommended Dosing: 120 mg (two 60 mg capsules) orally once daily at bedtime, with or without food, at approximately the same time each day.
Administration: Swallow capsules whole with water. Do not cut, crush, or chew.
Missed doses: If a dose is missed at bedtime, take the next dose as scheduled on the following day. Do not take two doses on the same day to make up for a missed dose.
Dosage Modification (Moderate CYP3A4 Inhibitors): Reduce dose to 60 mg (one capsule) once daily at bedtime.
Lab testing: Perform baseline and 3-month follow-up hepatic tests. Do not initiate or continue therapy if LFTs exceed certain thresholds. See Hepatotoxicity for more details. [1]

LONG-TERM SAFETY (OASIS 3)

BIBLIOGRAPHY

ELINZANETANT (LYNKUET®)