Adalacilib is indicated for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring a KRAS G12C mutation who have received at least one prior systemic therapy.

Adagracib instruction manual

Product Name: LuciAda

Manufacturer: Lucius Pharmaceuticals

Chinese name: Adagrasib English name: Adagrasib

Drug approval number: 02 L 1070/24

 

 

【Summary】

Adagrasib is an irreversible inhibitor of KRAS G12C, belonging to the RAS GTPase family. Its molecular formula is C32H35ClFN7O2 and its molecular weight is 604.1 g/mol.

The chemical name is {(2 S)-4-[7-(8-chloronaphthalen-1-yl)-2-{[(2 S)-1-methylpyrrolidin-2-yl]-methoxy}-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroacryloyl)piperazin-2-yl}acetonitrile.

 

【Indications】

Adaglasib is a RAS GTPase inhibitor indicated for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring a KRAS G12C mutation who have received at least one prior systemic therapy.

 

【Specification】

200 mg/tablet, 90 tablets/bottle.

 

【Storage】

Store at 20°C to 25°C (68°C to 77°F); short-distance transport is permitted at a temperature range of 15 to 30°C (59–86°F).

 

【Usage and Dosage】

1. Patient selection

Patients with locally advanced or metastatic NSCLC were selected for treatment with LuciAda based on the presence of KRASG12C mutations in plasma or tumor specimens. If the mutation was not detected in the plasma specimen, tumor tissue was tested.

Information about FDA-approved tests for detecting KRASG12C mutations can be found at https://www.fda.gov/CompanionDiagnostics

2. Recommended dosage

The recommended dose of LuciAda is 600 mg orally twice daily until disease progression or unacceptable toxicity.

Take LuciAda at the same time each day with or without food. Swallow the tablet whole. Do not chew, crush, or break the tablet.

If vomiting occurs after taking LuciAda, do not take an additional dose. Resume dosing at the next scheduled time.

If a dose is inadvertently missed, skip the dose if more than 4 hours have passed since the scheduled time of administration. Resume the dose at the next scheduled time.

3. Dose adjustment for adverse reactions

Recommended dose reductions for adverse reactions are shown in Table 1. If adverse reactions occur, a maximum of 2 dose reductions are allowed. Permanently discontinue LuciAda in patients who cannot tolerate 600 mg once daily.

Table 1: LuciAda dose reduction recommendations for adverse reactions

Recommended dose adjustments for adverse reactions are shown in Table 2.

Table 2: LuciAda dose adjustment recommendations for adverse reactions

ALT = alanine aminotransferase; AST = aspartate aminotransferase; ULN = upper limit of normal

*Grading defined according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0

 

【Warnings and Precautions】

1. Gastrointestinal adverse reactions

LuciAda can cause severe gastrointestinal adverse reactions.

In the pooled safety population [see ADVERSE REACTIONS], serious gastrointestinal adverse reactions observed were gastrointestinal bleeding at an incidence of 3.8%, including 0.8% grade 3 or 4 events, gastrointestinal obstruction in 1.6% of patients, including 1.4% grade 3 or 4 events, colitis in 0.5% of patients, including 0.3% grade 3 events, ileus in 0.5% of patients, and stricture in 0.3% of patients. In addition, nausea, diarrhea, or vomiting occurred in 89% of 366 patients, of which 9% were grade 3. Twenty-nine percent of patients had their dose interrupted or reduced due to nausea, diarrhea, or vomiting, and adagrasib was permanently discontinued in 0.3% of patients.

Monitor and manage patients with supportive care, including antidiarrheal medications, antiemetics, or fluid replacement, as indicated. Withhold, reduce, or permanently discontinue LuciAda based on severity [see Dosage and Administration].

2. QTc interval prolongation

LuciAda may cause QTc interval prolongation, which may increase the risk of ventricular tachyarrhythmias (e.g., torsades de pointes) or sudden death.

In the pooled safety population [see ADVERSE REACTIONS], of the 366 patients who had at least one post-baseline electrocardiogram (ECG) assessment, 6% had a mean QTc ≥ 501 ms and 11% had a QTc prolongation > 60 ms from baseline. LuciAda can cause concentration-dependent prolongation of the QTc interval.

Avoid concomitant use of LuciAda with other products known to prolong the QTc interval. [See Drug Interactions.] Avoid use of LuciAda in patients with congenital long QT syndrome and patients with concurrent QTc prolongation.

Monitor ECG and electrolytes prior to initiating LuciAda therapy, during concomitant use, and as clinically indicated in patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, and in patients who cannot avoid concomitant medications known to prolong the QT interval. Withhold, reduce dose, or permanently discontinue LuciAda based on severity [see DOSAGE AND ADMINISTRATION].

3. Liver toxicity

LuciAda can cause hepatotoxicity, potentially leading to drug-induced liver injury and hepatitis.

In the pooled safety population of 366 patients [see ADVERSE REACTIONS], drug-induced liver injury was reported in 0.3% of patients, of which 0.3% were Grade 3. A total of 32% of patients treated with adagrasib experienced elevated alanine aminotransferase (ALT)/elevated aspartate aminotransferase (AST); 5% were Grade 3 and 0.5% were Grade 4. The median time to the first occurrence of elevated ALT/AST was 3 weeks (range: 0.1-48 weeks). The overall incidence of hepatotoxicity was 37%, with 7% being Grade 3 or 4. Hepatotoxicity leading to dose interruption or dose reduction occurred in 12% of patients. Adagrasib was discontinued due to hepatotoxicity in 0.5% of patients.

Monitor liver laboratory tests (AST, ALT, alkaline phosphatase, and total bilirubin) prior to initiating LuciAda therapy and monthly for 3 months, or more frequently as clinically indicated in patients who develop transaminase elevations. Reduce, interrupt, or permanently discontinue LuciAda based on severity [see Dosage and Administration and Adverse Reactions].

4. Interstitial lung disease/non-infectious pneumonia

LuciAda can cause interstitial lung disease (ILD)/non-infectious pneumonitis, which may be fatal.

In the pooled safety population [see Adverse Reactions], ILD/non-infectious pneumonia occurred in 4.1% of patients, 1.4% were Grade 3 or 4, and one case was fatal. The median time to first onset of ILD/non-infectious pneumonia was 12 weeks (range: 5-31 weeks). 0.8% of patients discontinued Adagrasib due to ILD/non-infectious pneumonia.

During LuciAda treatment, monitor patients for new or worsening respiratory symptoms suggestive of ILD/pneumonitis (e.g., dyspnea, cough, fever). Withhold LuciAda in patients with suspected ILD/non-infectious pneumonitis and permanently discontinue LuciAda if no other underlying cause of ILD/non-infectious pneumonitis is found [see Dosage and Administration].

 

【 Adverse Reactions 】

1. Gastrointestinal adverse reactions [see Warnings and Precautions]

2. QTc interval prolongation [see Warnings and Precautions]

3. Hepatotoxicity [see Warnings and Precautions]

4. Interstitial lung disease (ILD)/non-infectious pneumonitis [see Warnings and Precautions]

Specific adverse reactions are shown in the table below:

*Grouped terms.

1 Hepatotoxicity included mixed liver injury, increased blood alkaline phosphatase, increased alanine aminotransferase, increased aspartate aminotransferase, increased liver function tests, increased blood bilirubin, and increased conjugated bilirubin.

2 Renal damage includes acute kidney injury and increased blood creatinine.

 

【Drug Interactions】

1. Effects of other drugs on LuciAda

a. Strong CYP3A4 inducers

Avoid concomitant use of LuciAda with strong CYP3A inducers.

Adagrasib is a CYP3A4 substrate. Coadministration of LuciAda with strong CYP3A inducers may decrease the exposure of adagrasib [see Clinical Pharmacology (12.3)], which may reduce the effectiveness of LuciAda.

b. Strong CYP3A4 inhibitors

Avoid coadministration of LuciAda with strong CYP3A inhibitors until adagrasib concentrations reach steady state (approximately after 8 days).

Adagrasib is a CYP3A4 substrate. If adagrasib concentrations have not yet reached steady state, concomitant use of strong CYP3A inhibitors will increase adagrasib concentrations [see Clinical Pharmacology (12.3)], which may increase the risk of LuciAda adverse reactions.

2. LuciAda’s impact on other drugs

a. Sensitive CYP3A substrates

Avoid concomitant use of LuciAda with sensitive CYP3A substrates unless otherwise recommended in the prescribing information for these substrates.

Adagrasib is a CYP3A inhibitor. Coadministration with LuciAda increases the exposure of CYP3A substrates, which may increase the risk of adverse reactions related to these substrates.

b. CYP2C9 sensitive substrates

Avoid coadministration of LuciAda with sensitive CYP2C9 substrates where minimal concentration changes could result in serious adverse reactions unless otherwise recommended in the prescribing information for these substrates.

Adagrasib is a CYP2C9 inhibitor. Coadministration with LuciAda increases the exposure of CYP2C9 substrates, which may increase the risk of adverse reactions related to these substrates.

c. CYP2D6 sensitive substrates

Avoid coadministration of LuciAda with sensitive CYP2D6 substrates, where small changes in concentration may result in serious adverse reactions, unless otherwise recommended in the prescribing information for these substrates.

Adagrasib is a CYP2D6 inhibitor. Coadministration with LuciAda increases the exposure of CYP2D6 substrates, which may increase the risk of adverse reactions related to these substrates.

d. P-gp substrate

Avoid concomitant use of LuciAda with P-gp substrates where minimal changes in concentration may result in serious adverse reactions unless otherwise recommended in the prescribing information for these substrates.

Adagrasib is a P-gp inhibitor. Coadministration with LuciAda increases exposure to P-gp substrates, which may increase the risk of adverse reactions related to these substrates.

3. Drugs that prolong the QTc interval

Avoid concomitant use of LuciAda with other products known to prolong the QTc interval. If concomitant medication cannot be avoided, monitor ECGs and electrolytes prior to initiating LuciAda treatment, during concomitant medication, and as clinically indicated [see WARNINGS AND PRECAUTIONS]. Discontinue LuciAda if QTc interval > 500 ms or change from baseline > 60 ms [see DOSAGE AND ADMINISTRATION].

Adagrasib can cause QTc interval prolongation. Concomitant use of LuciAda with other products that prolong the QTc interval may result in substantial QTc interval prolongation and adverse reactions associated with QTc interval prolongation, including torsades de pointes, other serious arrhythmias, and sudden death [see WARNINGS AND PRECAUTIONS].

【Use in special populations】

1. Pregnancy

Risk Summary

There are no available data on the use of LuciAda in pregnant women. In animal reproduction studies, oral administration of adagrasib to pregnant rats and rabbits during organogenesis at levels below the human exposure (recommended dose of 600 mg twice daily) did not cause adverse developmental effects or embryo-fetal mortality (see Data).

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

data

Animal data

In a rat embryo-fetal development study, oral administration of adagrasib once daily to pregnant rats during the period of organogenesis resulted in maternal toxicity (reduced body weight and food intake, and adverse clinical signs leading to moribundity and premature euthanasia) and decreased fetal body weights at a dose level of 270 mg/kg (approximately 2 times the recommended dose of 600 mg twice daily based on body surface area [BSA]). Adagrasib induces bone

Deformities (e.g., bowed limbs) and skeletal abnormalities (e.g., bowed scapulae, wavy ribs, and supernumerary short cervical ribs) observed at the 270 mg/kg dose were secondary to maternal toxicity and reduced fetal weights.

In a rabbit embryo-fetal development study, oral administration of adagrasib once daily during organogenesis resulted in reduced fetal body weights and increased frequency of non-ossified sternal pits at 30 mg/kg (approximately 0.11 times the human exposure based on the area under the curve [AUC] at the clinical dose of 600 mg twice daily). These skeletal changes were associated with maternal toxicity, including decreased mean body weight and reduced food intake. Adagrasib exposures did not cause adverse developmental effects and did not affect embryo-fetal survival in rabbits at doses up to 30 mg/kg once daily.

2. Lactation

Risk Summary

There are no data regarding the presence of adagrasib or its metabolites in human milk, the effects on the breastfed infant, or milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with LuciAda and for 1 week after the final dose.

3. Women and men of fertile age

Infertility

Based on findings from animal studies, LuciAda may impair fertility in females and males of reproductive potential.

4. Medication for children

The safety and effectiveness of LuciAda in pediatric patients have not been established.

5. Medication for elderly patients

Of the 116 patients who received adagrasib 600 mg orally twice daily in KRYSTAL-1, 49% (57 patients) were ≥ 65 years of age. No overall differences in safety or effectiveness were observed between elderly and younger patients.