ADADX Adagrasib Tablets

[ Name] Adagrasib Tablets

[Specification] 200 mg/tablet; 90 tablets/bottle.

[Manufacturer] Bigbear Pharmaceutical Laos

[Overview]

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

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

[Indications]

Adagrasib 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.

[Storage]

Store at 20°C to 25°C (68°F to 77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F).

[Dosage and Administration]

1. Patient Selection

Select patients with locally advanced or metastatic NSCLC for treatment with Adagrasib based on the presence of a KRAS G12C mutation in plasma or tumor specimens. If a mutation is not detected in a plasma specimen, test tumor tissue.

Information on FDA-approved tests for the detection of KRAS G12C mutations is available at https://www.fda.gov/CompanionDiagnostics.

2. Recommended Dosage

The recommended dosage of Adagrasib is 600 mg orally twice daily until disease progression or unacceptable toxicity occurs.

Take Adagrasib at the same time every day, with or without food. Swallow tablets whole. Do not chew, crush, or split the tablets.

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

If a dose is missed, and more than 4 hours have elapsed since the scheduled time, skip the missed dose. Resume dosing at the next scheduled time.

3. Dosage Adjustments for Adverse Reactions

Recommended dose reductions for adverse reactions are shown in Table 1. If an adverse reaction occurs, up to two dose reductions are permitted. Permanently discontinue adagrasib in patients who are unable to tolerate 600 mg once daily.

Table 1: Recommended Adagrasib Dose Reductions for Adverse Reactions

Dose Reduction

Dose

First Dose Reduction

400 mg twice daily

Second Dose Reduction

600 mg once daily

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

Table 2: Recommended Adagrasib Dosage Adjustments for Adverse Reactions

Adverse Reaction

Severity

Dosage Adjustment

Nausea or vomiting despite appropriate supportive care (including antiemetic therapy)

[See Warnings and Precautions]

Grade 3 or 4

1. Withhold adagrasib until resolved to Grade ≤1 or to baseline.

2. Resume adagrasib at the next lower dose level.

Diarrhea despite appropriate supportive care (including antidiarrheal therapy)

[See Warnings and Precautions]

Grade 3 or 4

1. Withhold adagrasib until resolved to Grade ≤1 or to baseline.

2. Resume adagrasib at the next lower dose level.

QTc Interval Prolongation

[See Warnings and Precautions]

Absolute QTc > 500 ms OR increase from baseline > 60 ms

1. Withhold adagrasib until QTc interval is < 481 ms or returns to baseline.

2. Resume adagrasib at the next lower dose level. Signs or symptoms of Torsades de Pointes, polymorphic ventricular tachycardia, or severe or life-threatening arrhythmias

Permanently discontinue adagrasib.

Hepatotoxicity

[See Warnings and Precautions]

Grade 2 AST or ALT

Reduce adagrasib to the next lower dose level.

Grade 3 or 4 AST or ALT

1. Withhold adagrasib until recovery to ≤ Grade 1 or to baseline.

2. Resume adagrasib at the next lower dose level.

AST or ALT > 3 × ULN and total bilirubin > 2 × ULN, in the absence of other causes

Permanently discontinue adagrasib.

Interstitial Lung Disease (ILD)/Non-infectious Pneumonitis

[See Warnings and Precautions]

Any Grade

1. Withhold adagrasib if ILD/non-infectious pneumonitis is suspected.

2. Permanently discontinue adagrasib if:

ILD/non-infectious pneumonitis is confirmed.

Other Adverse Reactions

Grade 3 or 4

1. Withhold adagrasib until recovery to

≤ Grade 1 or to baseline.

2. Resume adagrasib at the next lower dose level.

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

Adagrasib can cause severe gastrointestinal adverse reactions. In the pooled safety population [see ADVERSE REACTIONS], observed serious gastrointestinal adverse reactions included gastrointestinal hemorrhage, occurring in 3.8% of patients (including 0.8% Grade 3 or 4 events); gastrointestinal obstruction, occurring in 1.6% of patients (including 1.4% Grade 3 or 4 events); colitis, occurring in 0.5% of patients (including 0.3% Grade 3 events); intestinal obstruction, occurring in 0.5% of patients; and stenosis, occurring in 0.3% of patients. Additionally, among 366 patients, 89% experienced nausea, diarrhea, or vomiting, with 9% of these events being Grade 3. Twenty-nine percent of patients required interruption of dosing or dose reduction due to nausea, diarrhea, or vomiting, and 0.3% of patients permanently discontinued adagrasib.

Monitor and manage patients with supportive care as indicated, including antidiarrheals, antiemetics, or fluid replacement. Withhold, reduce the dose of, or permanently discontinue adagrasib based on severity [see DOSAGE AND ADMINISTRATION].

2. QTc Interval Prolongation

Adagrasib can cause QTc interval prolongation, which increases the risk of ventricular tachyarrhythmias (e.g., Torsades de Pointes) or sudden death.

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

Avoid the concomitant use of adagrasib with other products known to prolong the QTc interval [see DRUG INTERACTIONS]. Avoid the use of adagrasib in patients with congenital long QT syndrome and in patients with concomitant QTc prolongation. Monitor ECG and electrolytes prior to initiating Adagrasib treatment, during concomitant use, and in patients with clinically indicated congestive heart failure, bradyarrhythmias, or electrolyte abnormalities, as well as in patients for whom concomitant use of known QT-interval-prolonging medications cannot be avoided. Depending on the severity, withhold, reduce the dose of, or permanently discontinue LuciAda [see Dosage and Administration].

3. Hepatotoxicity

LuciAda can cause hepatotoxicity, which may lead to drug-induced liver injury and hepatitis.

In the pooled safety population of 366 patients [see Adverse Reactions], 0.3% of patients reported drug-induced liver injury, of which 0.3% were Grade 3. A total of 32% of patients treated with Adagrasib experienced alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevations; 5% were Grade 3, and 0.5% were Grade 4. The median time to the first occurrence of ALT/AST elevation 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 permanently discontinued due to hepatotoxicity in 0.5% of patients.

Monitor liver laboratory tests (AST, ALT, alkaline phosphatase, and total bilirubin) prior to initiating Adagrasib treatment, monthly for 3 months, or as clinically indicated; monitor more frequently in patients who develop transaminase elevations. Depending on the severity, reduce the dose of, withhold, or permanently discontinue Adagrasib [see Dosage and Administration and Adverse Reactions].

4. Interstitial Lung Disease/Non-infectious Pneumonitis

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

In the pooled safety population [see Adverse Reactions], ILD/non-infectious pneumonitis occurred in 4.1% of patients, with 1.4% being Grade 3 or 4, and one case being fatal. The median time to the 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 treatment with Adagrasib, monitor patients for new or worsening respiratory symptoms suggestive of ILD/pneumonia (e.g., dyspnea, cough, fever). Withhold LuciAda in patients with suspected ILD/non-infectious pneumonia; permanently discontinue Adagrasib if no other potential causes of ILD/non-infectious pneumonia are identified [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 Pneumonia [see Warnings and Precautions]

Specific adverse reactions are listed in the table below:

*Grouped term.

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

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

【Drug Interactions】

1. Effects of Other Drugs on Adagrasib

a. Strong CYP3A4 Inducers

Avoid concomitant use of Adagrasib with strong CYP3A4 inducers.

Adagrasib is a CYP3A4 substrate. Concomitant use of Adagrasib with strong CYP3A inducers may decrease Adagrasib exposure [see Clinical Pharmacology (12.3)], which may reduce the efficacy of Adagrasib.

b. Strong CYP3A4 Inhibitors

Avoid concomitant use of Adagrasib with strong CYP3A inhibitors until Adagrasib concentrations reach steady state (after approximately 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 adagrasib-related adverse reactions.

2. Effects of LuciAda on Other Drugs

a. Sensitive CYP3A Substrates

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

Adagrasib is a CYP3A inhibitor. Concomitant use with adagrasib increases the exposure of CYP3A substrates, which may increase the risk of adverse reactions associated with these substrates.

b. Sensitive CYP2C9 Substrates

Avoid concomitant use of adagrasib with sensitive CYP2C9 substrates where minimal changes in concentration may lead to serious adverse reactions, unless otherwise recommended in the prescribing information for these substrates.

Adagrasib is a CYP2C9 inhibitor. Concomitant use with adagrasib increases the exposure of CYP2C9 substrates, which may increase the risk of adverse reactions associated with these substrates.

c. Sensitive CYP2D6 Substrates

Avoid concomitant use of adagrasib with sensitive CYP2D6 substrates where minimal changes in concentration may lead to serious adverse reactions, unless otherwise recommended in the prescribing information for these substrates.

Adagrasib is a CYP2D6 inhibitor. Concomitant use with adagrasib increases the exposure of CYP2D6 substrates, which may increase the risk of adverse reactions associated with these substrates.

d. P-gp Substrates

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

Adagrasib is a P-gp inhibitor. Concomitant use with adagrasib increases the exposure of P-gp substrates, which may increase the risk of adverse reactions associated with these substrates. 3. Drugs Known to Prolong the QTc Interval

Avoid concomitant use of adagrasib with other products known to prolong the QTc interval. If concomitant use cannot be avoided, monitor ECGs and electrolytes prior to initiating adagrasib treatment, during concomitant use, and as clinically indicated [see Warnings and Precautions]. Discontinue adagrasib if the QTc interval is > 500 ms or increases by > 60 ms from baseline [see Dosage and Administration].

Adagrasib can cause QTc interval prolongation. Concomitant use of adagrasib with other products known to prolong the QTc interval may result in significant QTc interval prolongation and adverse reactions associated with QTc interval prolongation, including Torsades de Pointes, other serious ventricular arrhythmias, and sudden death [see Warnings and Precautions].

[Use in Specific Populations]

1. Pregnancy

Risk Summary

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

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.

Data

Animal Data

In an embryo-fetal development study in rats, oral administration of adagrasib once daily to pregnant rats during organogenesis 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]) resulted in maternal toxicity (decreased body weight and food consumption, as well as adverse clinical signs leading to moribundity and premature euthanasia) and decreased fetal body weight. Adagrasib induced skeletal variations.

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