Description for Lynkuet
LYNKUET is an NK1 and NK3 receptor antagonist.
The chemical name of elinzanetant is 2-[3,5-bis(trifluoromethyl)phenyl]-N-{4-(4-fluoro-2-methylphenyl)-6-[(7S,9aS)-7(hydroxymethyl)hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]pyridin-3-yl}-N,2-dimethylpropanamide having a molecular formula of C33H35F7N4O3 and a molecular weight of 668.7.
The structural formula of elinzanetant is:
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Elinzanetant is a white to yellowish powder and is practically insoluble in water and slightly soluble under acidic conditions.
Each LYNKUET (elinzanetant) capsule for oral use contains 60 mg of elinzanetant and the following inactive ingredients: all-rac-α-Tocopherol, caprylocaproyl macrogolglycerides, glycerol monocaprylocaprate, glycerol mono-oleate, and polysorbate 80. The capsule is composed of edible ink, ferric oxide red, ferric oxide yellow, gelatin, sorbitol specialglycerin, and titanium dioxide.
ADVERSE REACTIONS
The following clinically significant adverse reactions are described elsewhere in the labeling:
- Central Nervous System (CNS) Depressant Effect and Daytime Impairment [see Warnings and Precautions (5.1)]
- Hepatic Transaminase Elevations [see Warnings and Precautions (5.2)]
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 LYNKUET was evaluated in three randomized, double-blind, placebo-controlled, multicenter clinical trials (OASIS 1, OASIS 2, OASIS 3) in 1420 women. In OASIS 1 and OASIS 2 combined, 793 women received LYNKUET or placebo for 12 weeks. After the first 12 weeks, 341 women randomized to LYNKUET continued to receive LYNKUET for another 14 weeks, with a total treatment duration of up to 26 weeks. In OASIS 1 and OASIS 2 combined, 349 women received placebo for the first 12 weeks and 348 women switched to LYNKUET for the next 14 weeks. In OASIS 3, 627 women received LYNKUET or placebo for up to 52 weeks to evaluate long-term safety [see Clinical Studies (14)].
Common Adverse Reactions
In OASIS 1 and 2 combined, through the first 12 weeks, commonly reported adverse reactions in the LYNKUET group (≥2% and greater than in placebo) were headache, fatigue, gastroesophageal reflux disease, dizziness, nausea, and somnolence.
Similar adverse reactions were seen in OASIS 3. Table 2 shows adverse reactions reported in at least 2% of women and more commonly in women taking LYNKUET than placebo in OASIS 3.
Table 2. Common Adverse Reactions Reported in ≥ 2% in LYNKUET and Greater than Placebo, Weeks 1-52 (OASIS 3)
| Adverse Reaction | LYNKUET N=313 n (%) |
Placebo N=314 n (%) |
| Headache | 30 (9.6) | 22 (7.0) |
| Fatigue* | 23 (7.3) | 9 (2.9) |
| Dizziness† | 19 (6.1) | 6 (1.9) |
| Somnolence‡ | 16 (5.1) | 4 (1.3) |
| Abdominal pain§ | 14 (4.5) | 8 (2.5) |
| Rash¶ | 13 (4.2) | 5 (1.6) |
| Diarrhea | 12 (3.8) | 3 (1.0) |
| Muscle spasms# | 10 (3.2) | 2 (0.6) |
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*Includes asthenia. †Includes balance disorder, presyncope, vertigo, vertigo CNS origin, vertigo positional, and vestibular neuronitis. ‡Includes lethargy. §Includes abdominal discomfort, abdominal pain lower/upper. ¶Includes dermatitis, urticaria. #Includes muscle tightness. |
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Adverse Reactions Leading to Discontinuation
In OASIS 3, adverse reactions leading to treatment discontinuation (≥1% in LYNKUET and greater than placebo) were abdominal pain (1.6%), fatigue (1.6%), depression (1.6%) and headache (1.3%).
Photosensitivity
In the OASIS trials, mild to moderate events of photosensitivity occurred in 0.5% of patients receiving LYNKUET and 0.1% of patients receiving placebo. Onset of photosensitivity reactions ranged from day 1 to day 290. While discontinuation occurred in one patient, photosensitivity events in other patients resolved under continued treatment with LYNKUET [see Nonclinical Toxicology (13.2)].
Drug Interactions for Lynkuet
Effects of Other Drugs on LYNKUET
Elinzanetant is primarily metabolized via CYP3A4 enzyme. Table 3 describes drug interactions where concomitant use of another drug affects LYNKUET.
Table 3: Drug Interactions: Concomitant Use of Other Drugs Affect the Use of LYNKUET
| Strong and Moderate CYP3A4 Inhibitors1 | |
| Prevention or Management | Strong CYP3A4 Inhibitors and grapefruit (juice): Avoid concomitant use. |
| Moderate CYP3A4 Inhibitors: Reduce the LYNKUET dosage [see Dosage and Administration (2.2)]. | |
| Clinical Effect(s) | Strong and moderate CYP3A4 inhibitors increase elinzanetant exposure, which may increase the risk of LYNKUET-associated adverse reactions [see Clinical Pharmacology (12.3)]. |
| Strong and Moderate CYP3A4 Inducers1 | |
| Prevention or Management | Strong and moderate CYP3A4 inducers: Avoid concomitant use. |
| Clinical Effect(s) | Strong and moderate CYP3A4 inducers decrease elinzanetant exposure, which may reduce the effectiveness of LYNKUET. |
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1See www.fda.gov/CYPandTransporterInteractingDrugs for examples of strong and moderate CYP3A4 inhibitors, and CYP3A4 inducers. |
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Effects of LYNKUET on Other Drugs
CYP3A4 Substrates
Avoid concomitant use unless otherwise recommended in the Prescribing Information for CYP3A4 substrates where minimal concentration changes may lead to serious adverse reactions. See www.fda.gov/CYPandTransporterInteractingDrugs for examples of CYP3A4 substrates.
Elinzanetant is a weak inhibitor of CYP3A4. Concomitant use of LYNKUET increases exposure of CYP3A4 substrates [see Clinical Pharmacology (12.3)], which may increase the risk of adverse reactions related to these substrates.
Warnings for Lynkuet
Included as part of the PRECAUTIONS section.
Precautions for Lynkuet
Central Nervous System (CNS) Depressant Effect and Daytime Impairment
In the three OASIS trials, nervous system effects (including somnolence, fatigue, vertigo, dizziness and presyncope) occurred in 11.9% of patients on LYNKUET compared to 3.5% on placebo. [see also Adverse Reactions (6.1)].
Advise patients about the potential for somnolence and other nervous system effects. Advise patients who experience these effects to refrain from driving or engaging in hazardous occupations or activities until the effects have resolved [see Clinical Studies (14.3)].
Hepatic Transaminase Elevations
Elevations in serum transaminase (ALT and/or AST) concentrations equal to or greater than three times the ULN occurred in 0.6% of patients receiving LYNKUET and 0.4% of patients receiving placebo up to 12 weeks in three clinical trials. Perform baseline bloodwork (including ALT, AST, alkaline phosphatase, and total and direct bilirubin) prior to initiation of LYNKUET to evaluate for hepatic function and injury. Do not start therapy if serum transaminase concentration is equal to or exceeds two times the ULN or if the total bilirubin is equal to or exceeds two times the ULN. Perform followup evaluations of hepatic transaminase concentration 3 months after initiation of therapy.
Advise patients to discontinue LYNKUET immediately and seek medical attention including hepatic laboratory tests if they experience signs or symptoms that may suggest liver injury (new onset fatigue, decreased appetite, nausea, vomiting, pruritus, jaundice, pale feces, dark urine, or abdominal pain).
Discontinue LYNKUET if transaminase elevations exceed five times the ULN or if transaminase elevations exceed three times the ULN and total bilirubin exceeds two times the ULN.
Exclude alternative causes of hepatic laboratory test elevations.
Risk of Pregnancy Loss
LYNKUET is contraindicated for use in pregnancy [see Contraindications (4)]. Findings from animal studies suggest that LYNKUET can cause pregnancy loss or stillbirth. Exclude pregnancy in females of reproductive potential prior to initiating LYNKUET. Advise females of reproductive potential to use effective contraception during treatment with LYNKUET and for 2 weeks after stopping LYNKUET [see Use in Specific Populations (8.1, 8.3)].
Risk of Seizures in Patients with History of Seizures
Seizure was reported in one patient with a history of seizures in the clinical trials of LYNKUET. In addition, convulsions were observed in studies conducted in male and female rats [see Nonclinical Toxicology (13.2)]. Use LYNKUET with caution in patients with a history of seizures or with conditions that potentially lower the seizure threshold.
NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
In a 2-year carcinogenicity study in female rats, oral doses of elinzanetant ≥60 mg/kg/day (29-fold the total AUC(0-24) at the human therapeutic dose) increased the incidence of endometrial adenocarcinoma, the combination of malignant and benign endometrial tumors and squamous cell carcinoma of the uterus, and lymphomas of the hematolymphoid system. These effects were not observed at a dose representing 7-fold the total AUC(0-24) at the human therapeutic dose. The clinical significance of these findings is unknown.
In a 26-week carcinogenicity study in rasH2 transgenic mice, there was no evidence of drug-related carcinogenicity at 85 or 70 mg/kg/day in males or females, respectively.
Mutagenesis
Elinzanetant showed no genotoxic potential in bacterial mutation assay (Ames test), mouse lymphoma assay, and in-vivo bone marrow micronucleus test in rats. Additionally, the principal human metabolites of elinzanetant were negative for genotoxicity in vitro in the Ames and micronucleus test.
Animal Toxicology and/or Pharmacology
Repeat dose toxicity studies were conducted in rats and cynomolgus monkeys. The findings of clinical relevance are described below:
Reproductive organs (female)
In female rats, daily oral administration of elinzanetant for 4 weeks at 100 mg/kg (40-fold the AUC(0-24) at the human therapeutic dose) induced mucification of the vaginal epithelium, uterine atrophy, and persistent corpora lutea. In monkeys, twice daily oral administration of elinzanetant for 39 weeks at doses ≥60 mg/kg/day (2-fold the human therapeutic exposure) reduced cyclical ovarian activity.
Central Nervous System (CNS)
In male and female rats, twice daily oral administration of elinzanetant for 13 weeks induced involuntary muscle contractions starting around treatment day 24 and convulsions starting around day 34, when exposures in male and female rats were estimated to be ≥4-fold the AUC(0-24) at the human therapeutic dose.
In female rats, twice daily oral administration of elinzanetant for 2 years induced convulsions starting around treatment day 106, when exposures were estimated to be ≥17-fold the AUC(0-24) at the human therapeutic dose.
Skeletal muscle
In rats, twice daily oral administration of elinzanetant for 13 weeks at ≥100 mg/kg/day (equivalent to ≥16-fold the AUC(024) at human therapeutic dose) induced skeletal muscle degeneration and necrosis. These findings were not related to the convulsions presented by elinzanetant-treated rats in the same 13-week toxicity study (described under CNS above). A longer duration (26-week) toxicity study in rats as well as a follow up mechanistic study in male rats did not have any skeletal muscle findings. The clinical relevance of these findings is unknown.
Gastrointestinal system
In male and female monkeys, once daily oral administration of elinzanetant for 4 weeks at 60 mg/kg/day (4-fold the AUC(0-24) at human therapeutic exposure) caused loose/watery fecal consistency and reduced food intake. In three studies of male and female monkeys treated orally with elinzanetant for 13 to 39 weeks, gastrointestinal disturbances characterized by diarrhea were observed at doses ≥30 mg/kg/day (0.2-fold the AUC(0-24) at human therapeutic exposure). Diarrhea eventually led to dehydration, weight loss, and general ill-health in animals at doses of ≥60 mg/kg/day.
Photosensitivity
An in-vitro study demonstrated that elinzanetant has some potential for photosensitization. While studies of photosensitivity in animals were not conducted, there is evidence that elinzanetant distributes to and accumulates in melanin-containing tissues in the rats.
OVERDOSAGE
There is no specific antidote for LYNKUET. In the case of overdose, the individual should be closely monitored, and supportive treatment should be considered based on signs and symptoms.
Contraindications for Lynkuet
LYNKUET is contraindicated in pregnancy. Exposure to LYNKUET may cause pregnancy loss or stillbirth when administered during pregnancy [see Use in Specific Populations (8.1, 8.3)].
Clinical Pharmacology for Lynkuet
Mechanism of Action
LYNKUET 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).
Pharmacodynamics
Cardiac Electrophysiology
No clinically relevant prolongation of the QTc interval was observed after single oral administration of elinzanetant at doses up to 5 times the maximum recommended dose. However, QTc prolongation effect of elinzanetant when coadministered with strong CYP3A4 inhibitors has not been sufficiently characterized.
Pharmacokinetics
Elinzanetant Cmax and AUC increased in a greater than dose-proportional manner (20% to 50%) over the dose range from 40 to 160 mg once daily (0.33 to 1.33 times the highest recommended dose).
Elinzanetant steady state plasma concentrations were reached in 5 to 14 days after daily dosing.
Elinzanetant accumulation is <2-fold at the approved recommended dosage.
Absorption
Elinzanetant median (min-max) time to maximum plasma concentration (Tmax) is 1.0 hours (1-2.5 hours) at steady state. Elinzanetant absolute bioavailability is 52% following oral administration.
Effect of Food
No clinically significant differences in elinzanetant pharmacokinetics were observed following administration with a highcalorie, high-fat meal containing approximately 1000 calories (500-600 calories from fat, 250 calories from carbohydrates, and 150 calories from protein).
Distribution
The mean volume of distribution after intravenous administration at steady state of elinzanetant is 137 L. The plasma protein binding of elinzanetant is 99.7%. The blood-to-plasma ratio is between 0.6 and 0.7.
Elimination
Elinzanetant elimination half-life was approximately 45 hours in women with vasomotor symptoms. The clearance of elinzanetant after a single intravenous dose was 8.77 L/h.
Metabolism
Elinzanetant is primarily metabolized by CYP3A4 to yield three major active metabolites, M18/21, M27, and M30/34. These metabolites have similar potency for the human NK1 and NK3 receptors as compared to elinzanetant. The ratio of these metabolites to parent in plasma is approximately 0.39.
Excretion
Following a single oral dose of radiolabeled elinzanetant in healthy subjects, approximately 90% of the dose was recovered in feces (50% unchanged) and less than 1% with urine.
Specific Populations
No clinically significant differences in the pharmacokinetics of LYNKUET were observed based on race.
Patients with Renal Impairment
In patients with mild (eGFR 60 to <90 mL/min) renal impairment, mean elinzanetant Cmax increased 1.9-fold and AUC increased 1.6-fold. In patients with moderate (eGFR 30 to <60 mL/min) renal impairment, mean elinzanetant Cmax increased 1.8-fold and AUC increased 1.7-fold. In patients with severe (eGFR< 30 mL/min) renal impairment, mean elinzanetant Cmax increased 1.2-fold and AUC increased 1.1-fold.
Population pharmacokinetic analysis of the clinical trial data indicate similar exposure of elinzanetant in patients with mild and moderate renal impairment compared to patients with normal renal function.
Elinzanetant has not been studied in patients with end-stage renal disease (eGFR <15 mL/min) [see Use in Specific Populations (8.7)].
Patients with Hepatic Impairment
In patients with Child-Pugh Class A (mild) hepatic impairment, mean elinzanetant Cmax increased 1.2-fold and AUC(0-24) increased 1.5-fold. In patients with Child-Pugh Class B (moderate) hepatic impairment, mean elinzanetant Cmax and AUC(0-24) increased by 2.3-fold.
Elinzanetant has not been studied in patients with Child-Pugh Class C (severe) hepatic impairment [see Use in Specific Populations (8.6)].
Drug Interaction Studies
Clinical Studies and Model-Informed Approaches
No clinically significant differences in elinzanetant pharmacokinetics were observed when used concomitantly with esomeprazole (proton pump inhibitor). No clinically significant differences in the pharmacokinetics of the following oral drugs were observed when used concomitantly with elinzanetant: tamoxifen (substrate of CYP2D6, CYP3A4 and P-gp) and rosuvastatin (substrate of BCRP, OATP1B1/OATP1B3, and OAT3).
Strong CYP3A4 and P-gp inhibitors: Elinzanetant Cmax increased approximately 3.3-fold and AUC increased 6.3-fold following concomitant use with itraconazole 200 mg (strong CYP3A4 and P-gp inhibitor).
Moderate CYP3A4 Inhibitors: Elinzanetant Cmax and AUC are predicted to increase 2.0-fold and 3.0-fold, respectively, following concomitant use of elinzanetant 120 mg with erythromycin (moderate CYP3A4 inhibitor). PBPK predictions after co-administration of 60 mg elinzanetant [(see Dosage and Administration (2.3)] with the moderate CYP3A4 inhibitor erythromycin showed a 1.4-fold increase of elinzanetant AUC and no increase for Cmax when compared to 120 mg, the regular recommended elinzanetant dosage.
Weak CYP3A4 Inhibitors: Elinzanetant Cmax is predicted to increase 1.3-fold and AUC increase 1.5-fold following concomitant use with cimetidine (weak CYP3A4 inhibitor).
Moderate to Strong CYP3A4 Inducers: Elinzanetant Cmax reduced by 44% and AUC reduced by 64% following concomitant use with carbamazepine (moderate to strong CYP3A4 inducer) 600 mg administered twice daily.
Sensitive CYP3A4 Substrates: Elinzanetant increased midazolam (sensitive CYP3A4 substrate) Cmax 1.5-fold and AUC 1.8-fold.
In Vitro Studies
Cytochrome P450 (CYP450) Enzymes: Elinzanetant and its metabolites M18/21, M27, and M30/M34 inhibited CYP3A4 but did not inhibit CYP1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 2J2, or induce CYP1A2, 2B6, 2C19, or 3A4 at clinically relevant concentrations.
Transporter systems: Elinzanetant is a substrate for P-gp but not for OATP1A2, OATP2B1, BCRP, OATP1B1, OATP1B3, or MRP4. Elinzanetant and its metabolites M18/21, M27, and M30/M34 inhibited P-gp, BCRP, and BSEP in vitro but did not inhibit OAT1, OAT3, OCT1, OCT2, MATE2-K, or MRP2.
Patient Information for Lynkuet
Advise the patient to read the FDA-approved patient labeling (Patient Information).
CNS Depressant Effect and Daytime Impairment
Advise patients who experience somnolence and other nervous system effects to refrain from driving or engaging in hazardous occupations or activities until the effects have resolved [see Warnings and precaution (5.1) and Clinical Studies (14.3)].
Hepatic Transaminase Elevations
Advise patients that bloodwork to evaluate for hepatic functions and injury will be obtained at baseline and three months after initiating therapy.
Advise patients to discontinue LYNKUET immediately and seek medical attention including hepatic laboratory tests if they experience signs or symptoms that may suggest liver injury (new onset fatigue, decreased appetite, nausea, vomiting, pruritus, jaundice, pale feces, dark urine, or abdominal pain). [see Warnings and Precautions (5.2)].
Females of Reproductive Potential
Exclude pregnancy in females of reproductive potential prior to initiating LYNKUET. Advise females of reproductive potential to use effective contraception during treatment with LYNKUET and for two weeks after discontinuing treatment and to discontinue LYNKUET if pregnancy is confirmed [see Warnings and Precautions (5.3) and Use in Specific Populations (8.1, 8.3)].
Risk of Seizures in Patients with History of Seizures
Advise patients to report any history of seizures or conditions that potentially lower the seizure threshold. [see Warnings and Precautions (5.4)].
Important Administration Instructions
Advise patients to take LYNKUET once daily at bedtime with water and swallow capsules whole. Advise patients not to cut, crush or chew capsules [see Dosage and Administration (2.1)].
Instruct patients requiring a dosage modification (i.e., one 60 mg capsule once daily) to partially peel back the foil covering the blister cell to expose only one of the two capsules. Instruct patients to store the remaining capsule in the original blister card in the carton until the next dose [see Storage and Handling (16.2)].
Drug Interactions
Advise patients to report their use of any other prescription or nonprescription medications or dietary supplements [see Drug Interactions (7.1)].
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