Krazati adagrasib 200 mg Tablet, Coated, 180-count — NDC 80739-812-18 (Billing 80739-0812-18)
This is a package of 180 tablets of Krazati adagrasib 200 mg Tablet, Coated from Mirati Therapeutics, Inc, marketed since Dec 2022 and currently FDA-listed. It is the main listing for this product, which comes in 2 package sizes.
Identity & classification
Regulatory identifiers FDA, NLM and CMS codes for this package
Drug-database identifiers Medi-Span GPI and First Databank GCN / HICL / AHFS classification
- GSN (GCN sequence number): 084185
- GCN: 53379
- GPI-14 (Medi-Span): 21532410000320
- HICL (First Databank): 048522
- AHFS class code: 10:00.00.00
- RxCUI (RxNorm): 2625917
Where does this data come from?
- FDA openFDA NDC Directory · synced Oct 1, 2026
- FDA label on DailyMed · label index refreshed Oct 1, 2026
- RxNorm (NLM RxNav) · catalog refreshed Oct 1, 2026
- Medi-Span GPI (licensed)
- First Databank (licensed) · refreshed Oct 1, 2026
RxNorm drug class
This medicine belongs to the Other antineoplastic agents class.
Where does this data come from?
- RxClass (NLM) · catalog refreshed Oct 1, 2026
Clinical
Adagrasib is used to treat certain types of non-small cell lung cancer (NSCLC) that has spread to nearby tissues or to other parts of the body or cannot be removed by surgery in adults who have received at least one other treatment. Adagrasib is also used in combination with cetuximab (Erbitux) to treat a certain type of colon cancer that has spread to other parts of the body after other treatment(s). Adagrasib is in a class of medications called KRAS inhibitors. It works by blocking the action of the abnormal protein that signals cancer cells to multiply. This helps stop or slow the spread of...
Read the full MedlinePlus article ↗- Krazati is a targeted therapy — meaning it goes after a specific abnormality in your cancer cells rather than attacking all rapidly dividing cells the way traditional chemotherapy...
- What exactly is Krazati (adagrasib) and why was it prescribed to me?
- The most common side effects are nausea, diarrhea, and vomiting — these happen in the vast majority of people taking Krazati. Fatigue, muscle and joint pain, decreased appetite, an...
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Patient education
Supplement & herbal interactions
Some supplements/herbs that may interact with Adagrasib — tap one for details:
Where does this data come from?
- MedlinePlus (NLM) · refreshed Oct 1, 2026
- FDA label on DailyMed · label index refreshed Oct 1, 2026
Ask a licensed pharmacist directly — free, answered by our team.
Pricing
A drug doesn't have one price. Each row is a different public payment system, and none is what you'd pay at the counter — that depends on your insurance. The ⓘ on each row explains what it measures.
| Price system | Per each | Per package |
|---|---|---|
| Retail pharmacies payNADAC · weekly | Not in the retail survey — common for institutional, discontinued, or low-volume packs. | |
| Medicaid paysCMS SDUD · 12 mo | $125.06 | $22,509.94 / 180 tablets |
| Medicare drug plans payPart D · Q2 2026 | $124.75 | $22,455.47 / 180 tablets |
Where does this data come from?
- CMS NADAC weekly file
- CMS ASP pricing files · refreshed Sep 20, 2026
- CMS Medicaid State Drug Utilization Data · through Q1 2026
- CMS Part D plan pricing files · refreshed Sep 24, 2026
- VA National Acquisition Center price file
Packaging — all sizes for this product
| Package NDC | Description | Marketing start | Marketing end | Status |
|---|---|---|---|---|
| 80739-0812-12 80739-812-12 | 1 BOTTLE in 1 CARTON / 120 TABLET, COATED in 1 BOTTLE | 2022-12-12 | — | Active |
| 80739-0812-18 You're viewing this Main listing | 1 BOTTLE in 1 CARTON / 180 TABLET, COATED in 1 BOTTLE | 2022-12-12 | — | Active |
In Medicaid, this is the most-dispensed pack of this product — about 100% of fills over the last four reported quarters. See all packs ↓
Pack size FAQ
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How does this package differ from NDC 80739-0812-12?
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Therapeutic equivalents
| Product | Labeler | Pack | NADAC/unit | TE | Status | Price vs. this |
|---|---|---|---|---|---|---|
| Krazati 200 mgthis 80739-0812-18 | Mirati | 180 tablets | — | — | FDA listed | — |
Where does this data come from?
- FDA openFDA NDC Directory · synced Oct 1, 2026
- FDA Orange Book · refreshed Sep 3, 2026
- CMS NADAC weekly file
Availability & generic status
We did not find an FDA-approved generic match for this exact strength, form and route. Patent/protection dates below may affect future generic timing.
Why the date isn’t exact: Generic timing can change because patents may be challenged, settled, licensed, added, removed, or worked around with a narrower label — and FDA approval does not always mean a pharmacy can get the generic today.
🛈 What do these terms mean?
- Patent
- Legal protection listed in the Orange Book that may delay generic approval or launch. Issued by the U.S. Patent & Trademark Office.
- Substance patent
- Covers the active drug molecule itself — the hardest to design around. A generic generally can’t launch until it expires.
- Formulation (product) patent
- Covers a specific formulation or dosage form. A generic can sometimes work around it with a different formulation.
- Method-of-use patent
- A patent covering one specific approved use of the drug — not necessarily the whole molecule. A generic can sometimes launch with a “skinny label” that carves out the protected use and keeps the others.
- Skinny label
- A generic label that omits a still-patented use when the FDA allows it — letting a generic reach the market for the unprotected uses.
- Exclusivity
- FDA-granted marketing protection, separate from patents — e.g. 5-yr new chemical entity, 7-yr orphan drug, or a +6-month pediatric extension.
- Paragraph IV
- A generic applicant’s formal challenge to a listed patent. It can potentially lead to earlier generic entry, but often involves litigation or a settlement.
- RLD / RS
- Reference Listed Drug — the brand product the FDA uses as the reference for generic applications. Reference Standard — the product the FDA expects generics to compare against in bioequivalence testing.
- TE / AB rating
- FDA therapeutic-equivalence rating. An AB rating generally means the FDA considers a generic therapeutically equivalent to — and substitutable for — the brand.
- LOE (loss of exclusivity)
- The latest patent or exclusivity currently listed — the loss-of-exclusivity / latest-listed-protection date shown on this page. Paragraph-IV challenges and settlements can move the real date earlier; FDA approval and a manufacturer’s decision to market can move it later.
Built from the FDA Orange Book. The bars above are scaled to each protection’s expiry; the red LOE marker is the last one to lapse.
| Patent | Type | Use code | Expires |
|---|---|---|---|
| US 12336995 ↗ | Method of use | U-3953 | Feb 5, 2041 |
| US 10689377 ↗ | Drug substance | U-3490 | May 17, 2037 |
| US 10689377 ↗ | Drug substance | U-3953 | May 17, 2037 |
| US 12281113 ↗ | Drug substance | — | Sep 10, 2041 |
| US 12653789 ↗ | Drug product | — | Aug 21, 2043 |
| US 12383503 ↗ | Drug product | — | Aug 21, 2043 |
| Code | What it grants | Expires |
|---|---|---|
| NCE | New Chemical Entity (5-year) | Dec 12, 2027 |
| ODE-352 | Orphan Drug Exclusivity (7-year) | Dec 12, 2029 |
Is there a generic version of KRAZATI 200 MG TABLET?
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Where does this data come from?
- FDA Orange Book · refreshed Sep 3, 2026
What it looks like
Where does this data come from?
- FDA label on DailyMed · label index refreshed Oct 1, 2026
Inactive Ingredients / Excipients
Inactive ingredients, also called excipients, are components of the drug product other than the active ingredient. They may include fillers, dyes, coatings, preservatives, flavors, or other formulation ingredients.
💡 Tap an ingredient (hover on desktop) to see what it is and why it’s used.
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UNII 2S7830E561
Crospovidone is a synthetic polymer derived from povidone. It acts as a disintegrant, helping the tablet or capsule break apart quickly in the stomach so the active ingredient can be absorbed.
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UNII 36SFW2JZ0W
Hypromellose 2910 is a plant-based thickening agent derived from cellulose. In medicines, it forms a protective coating on tablets or capsules and controls how quickly the drug dissolves and releases into your body.
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UNII 70097M6I30
Magnesium stearate is a salt made from magnesium and stearic acid, a fatty substance. It's used in tablets and capsules as a lubricant and glidant to help ingredients flow smoothly during manufacturing and prevent sticking.
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UNII 7CVR7L4A2D
A starch-derived carbohydrate produced by breaking down corn, potato, or tapioca starch. It functions as a filler and binder to give the medicine bulk and texture, and sometimes as a mild sweetener or texture enhancer in powders and tablets.
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UNII 3OWL53L36A
A natural sugar alcohol derived from seaweed or synthesized in the lab. It's used as a filler to add bulk, a sweetener in sugar-free formulas, and a disintegrant to help tablets break apart in the stomach.
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UNII C9H2L21V7U
A fat derived from coconut or palm oil containing shorter fatty acid chains. It serves as a solvent and carrier to help dissolve or suspend active ingredients, improving absorption and stability in liquid formulations.
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UNII OP1R32D61U
Microcrystalline cellulose is a purified form of cellulose, a natural fiber from plant sources. It acts as a binder and filler in tablets and capsules, helping hold ingredients together and give the medicine its shape and size.
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UNII VH2XOU12IE
Polydextrose is a synthetic polymer made from dextrose (sugar) that acts as a bulking agent and filler in medicines. It helps give tablets and capsules proper volume and texture while often adding slight sweetness.
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UNII ETJ7Z6XBU4
Silicon dioxide is a naturally occurring mineral used as a glidant and anti-caking agent. It helps powder ingredients flow smoothly and prevents clumping during manufacturing and storage.
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UNII 7SEV7J4R1U
A powder made from a naturally occurring mineral. In medicines, talc works as a glidant and anti-caking agent, helping tablets and capsules flow smoothly during manufacturing and preventing clumping.
10 inactive ingredients listed in the exact product block matched to this NDC.
Where does this data come from?
ingredient classCode="IACT" elements from the exact product block matched by this NDC. Label-section narrative from DailyMed / the openFDA label index is shown separately when available.- FDA label on DailyMed · label index refreshed Oct 1, 2026
- FDA openFDA NDC Directory · synced Oct 1, 2026
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Manufacturer & labeler
Where does this data come from?
- FDA openFDA NDC Directory · synced Oct 1, 2026
- Drugs@FDA
Full prescribing information FDA SPL
🎯 Indications and Usage ▾
1 INDICATIONS AND USAGE KRAZATI is an inhibitor of the RAS GTPase family indicated for: Non-small cell lung cancer (NSCLC)* • As a single agent, for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic NSCLC, as determined by an FDA-approved test, who have received at least one prior systemic therapy. ( 1.1 ) Colorectal cancer (CRC)* • In combination with cetuximab, for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic CRC, as determined by an FDA-approved test, who have received prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy.
( 1.2 ) *These indications are approved under accelerated approval based on objective response rate (ORR) and duration of response (DOR). Continued approval for these indications may be contingent upon verification and description of a clinical benefit in confirmatory trials. ( 1.1 , 1.2 )
1.1KRAS G12C-Mutated Locally Advanced or Metastatic Non-Small Cell Lung Cancer KRAZATI, as a single-agent, is indicated for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC), as determined by an FDA-approved test [see Dosage and Administration (2.1) ] , who have received at least one prior systemic therapy. This indication is approved under accelerated approval based on objective response rate (ORR) and duration of response (DOR) [see Clinical Studies (14.1) ].
Continued approval for this indication may be contingent upon verification and description of a clinical benefit in a confirmatory trial.
1.2KRAS G12C-Mutated Locally Advanced or Metastatic Colorectal Cancer KRAZATI in combination with cetuximab is indicated for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic colorectal cancer (CRC), as determined by an FDA-approved test [see Dosage and Administration (2.1) ] , who have received prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. This indication is approved under accelerated approval based on ORR and DOR [see Clinical Studies (14.2) ] .
Continued approval for this indication may be contingent upon verification and description of a clinical benefit in a confirmatory trial.
⏱️ Dosage and Administration ▾
2 DOSAGE AND ADMINISTRATION • Recommended dosage as a single agent for NSCLC and in combination with cetuximab for CRC: 600 mg orally twice daily. ( 2.2 ) • Swallow tablets whole with or without food. ( 2.2 )
2.1Patient Selection Non-Small Cell Lung Cancer Select patients for treatment of locally advanced or metastatic NSCLC with KRAZATI based on the presence of KRAS G12C mutation in plasma or tumor specimens [see Clinical Studies (14.1) ] . If no mutation is detected in a plasma specimen, test tumor tissue. Colorectal Cancer Select patients for treatment of locally advanced or metastatic CRC with KRAZATI based on the presence of KRAS G12C mutation in tumor specimens [see Clinical Studies (14.2) ] .
Information on FDA-approved tests for the detection of a KRAS G12C mutation is available at: https://www.fda.gov/CompanionDiagnostics
2.2Recommended Dosage The recommended dosage of KRAZATI as a single agent or in combination with cetuximab is 600 mg orally twice daily until disease progression or unacceptable toxicity. Refer to the cetuximab prescribing information for cetuximab dosage information [see Clinical Studies (14.2) ] . Take KRAZATI at the same time every day with or without food [see Clinical Pharmacology (12.3) ].
Swallow tablets whole. Do not chew, crush or split tablets. If vomiting occurs after taking KRAZATI, do not take an additional dose.
Resume dosing at the next scheduled time. If a dose is inadvertently missed, it should be skipped if greater than 4 hours have elapsed from the expected dosing time. Resume dosing at the next scheduled time.
2.3Dosage Modifications for Adverse Reactions Recommended dose reductions for adverse reactions for use of KRAZATI as a single agent or in combination with cetuximab are outlined in Table 1. If adverse reactions occur, a maximum of two dose reductions are permitted. Permanently discontinue KRAZATI in patients who are unable to tolerate 600 mg once daily.
Table 1: Recommended KRAZATI Dosage Reductions for Adverse Reactions Dose Reduction Dosage First dose reduction 400 mg twice daily Second dose reduction 600 mg once daily Refer to the cetuximab prescribing information for dose modifications for adverse reactions associated with cetuximab. When KRAZATI is administered in combination with cetuximab, withhold or permanently discontinue cetuximab when KRAZATI is withheld or permanently discontinued. Treatment with KRAZATI as a single agent may be continued if cetuximab is permanently discontinued. [see Clinical Pharmacology (12.1) , Clinical Studies (14.2) ] .
The recommended dosage modifications for adverse reactions are provided in Table 2. Table 2: Recommended KRAZATI Dosage Modifications for Adverse Reactions ALT = alanine aminotransferase; AST = aspartate aminotransferase; ILD = Interstitial Lung Disease; ULN = upper limit of normal Adverse Reaction Severity Grading defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. Dosage Modification When KRAZATI is administered in combination with cetuximab, withhold or permanently discontinue treatment with cetuximab when withholding or permanently discontinuing treatment with KRAZATI.
Nausea or vomiting despite appropriate supportive care (including anti-emetic therapy) [see Warnings and Precautions (5.1) ] Grade 3 or 4 • Withhold KRAZATI until recovery to ≤ Grade 1 or return to baseline. • Resume KRAZATI at the next lower dose level. Diarrhea despite appropriate supportive care (including anti-diarrheal therapy) [see Warnings and Precautions (5.1) ] Grade 3 or 4 • Withhold KRAZATI until recovery to ≤ Grade 1 or return to baseline. • Resume KRAZATI at the next lower dose level. QTc Interval Prolongation [see Warnings and Precautions (5.2) ] QTc absolute value greater than 500 ms or Greater than an increase of 60 ms from baseline • Withhold KRAZATI until QTc interval less than 481 ms or return to baseline. • Resume KRAZATI at the next lower dose level.
Torsade de pointes, poly… [Excerpted — this section continues on DailyMed.]
💊 Dosage Forms and Strengths ▾
3 DOSAGE FORMS AND STRENGTHS Tablets: 200 mg, oval shaped, white to off-white, immediate release film coated tablets with "200" on one side and stylized "M" on the opposite side. Tablets: 200 mg. ( 3 )
⛔ Contraindications ▾
4 CONTRAINDICATIONS None. None. ( 4 )
⚠️ Warnings and Cautions ▾
5 WARNINGS AND PRECAUTIONS • Gastrointestinal Adverse Reactions : Monitor patients for diarrhea, nausea and vomiting and provide supportive care as needed. Withhold, reduce the dose or permanently discontinue based on severity. ( 2.3 , 5.1 ) • QTc Interval Prolongation: Avoid concomitant use of KRAZATI with other products with a known potential to prolong the QTc interval.
Monitor ECG and electrolytes particularly potassium and magnesium, in patients at risk, and in patients taking medications known to prolong the QT interval. Correct electrolyte abnormalities. Withhold, reduce the dose, or permanently discontinue based on severity.
( 2.3 , 5.2 ) • Hepatotoxicity: Monitor liver laboratory tests prior to the start of KRAZATI and monthly for 3 months after and as clinically indicated. Reduce the dose, withhold, or permanently discontinue based on severity. ( 2.3 , 5.3 ) • Interstitial Lung Disease (ILD) / Pneumonitis: Monitor for new or worsening respiratory symptoms.
Withhold KRAZATI for suspected ILD/pneumonitis and permanently discontinue if no other potential causes of ILD/pneumonitis are identified. ( 2.3 , 5.4 )
5.1Gastrointestinal Adverse Reactions KRAZATI can cause severe gastrointestinal adverse reactions. In the pooled safety population [see Adverse Reactions (6.1) ] , who received single-agent KRAZATI, serious gastrointestinal adverse reactions observed were gastrointestinal bleeding in 3.8% including 0.8% Grade 3 or 4, gastrointestinal obstruction in 1.6% including 1.4% Grade 3 or 4, colitis in 0.5% including 0.3% Grade 3, ileus in 0.5%, and stenosis in 0.3%. In addition, nausea, diarrhea, or vomiting occurred in 89% of 366 patients, including 9% Grade 3.
Nausea, diarrhea, or vomiting led to dosage interruption or dose reduction in 29% of patients and permanent discontinuation of adagrasib in 0.3%. In patients who received KRAZATI in combination with cetuximab [see Adverse Reactions (6.1) ] , serious gastrointestinal adverse reactions included gastrointestinal bleeding in 8.5% including 1.1% Grade 3 or 4, gastrointestinal obstruction in 5.3% including 5.3% Grade 3 or 4, colitis in 1.1% including 1.1% Grade 3 and ileus in 1.1%. In addition, nausea, diarrhea, or vomiting occurred in 92% of 94 patients, including 6% Grade 3.
Nausea, diarrhea, or vomiting led to adagrasib dose interruption or dose reduction in 23% of patients. Monitor and manage patients using supportive care, including antidiarrheals, antiemetics, or fluid replacement, as indicated. Withhold, reduce the dose, or permanently discontinue KRAZATI based on severity [see Dosage and Administration (2.3) ].
5.2QTc Interval Prolongation KRAZATI can cause QTc interval prolongation, which can increase the risk for ventricular tachyarrhythmias (e.g., torsades de pointes) or sudden death . In the pooled safety population [see Adverse Reactions (6.1) ] who received single-agent KRAZATI , 6% of 366 patients with at least one post-baseline electrocardiogram (ECG) assessment had an average QTc ≥ 501 msec and 11% of patients had an increase from baseline of QTc > 60 msec. KRAZATI causes concentration-dependent increases in the QTc interval [see Clinical Pharmacology (12.2) ] .
In patients who received KRAZATI in combination with cetuximab [see Adverse Reactions (6.1) ] , 5% of 93 patients with at least one post-baseline electrocardiogram (ECG) assessment had an average QTc ≥ 501 msec and 16% of patients had an increase from baseline of QTc > 60 msec. Avoid concomitant use of KRAZATI with other products with a known potential to prolong the QTc interval [see Drug Interactions (7.3) and Clinical Pharmacology (12.2) ]. Avoid use of KRAZATI in patients with congenital long QT syndrome and in patients with concurrent QTc prolongation.
Monitor ECGs and electrolytes, particularly potassium and magnesium, prior to starting KRAZATI, during concomitant use, and as clinically indicated in patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, and in… [Excerpted — this section continues on DailyMed.]
🤒 Adverse Reactions ▾
6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.1) ] • QTc Interval Prolongation [see Warnings and Precautions (5.2) ] • Hepatotoxicity [see Warnings and Precautions (5.3) ] • Interstitial Lung Disease (ILD)/Pneumonitis [see Warnings and Precautions (5.4) ] • Single agent use in NCSLC: The most common adverse reactions (≥ 25%) were nausea, diarrhea, vomiting, fatigue, musculoskeletal pain, hepatotoxicity, renal impairment, edema, dyspnea, and decreased appetite.
The most common (≥ 2%) Grade 3 or 4 laboratory abnormalities were decreased lymphocytes, decreased hemoglobin, increased alanine aminotransferase, increased aspartate aminotransferase, hypokalemia, hyponatremia, increased lipase, decreased leukocytes, decreased neutrophils and increased alkaline phosphatase. ( 6.1 ) • In combination with cetuximab in CRC: The most common adverse reactions (≥ 25%) were rash, nausea, diarrhea, vomiting, fatigue, musculoskeletal pain, hepatotoxicity, headache, dry skin, abdominal pain, decreased appetite, edema, anemia, and cough.
The most common (≥ 2%) Grade 3 or 4 laboratory abnormalities were decreased lymphocytes, decreased potassium, decreased magnesium, decreased hemoglobin, increased aspartate aminotransferase, increased lipase, decreased albumin, and increased alanine aminotransferase. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
6.1Clinical 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 practice. The pooled safety population described in the WARNINGS AND PRECAUTIONS reflect exposure to adagrasib as a single agent at 600 mg orally twice daily in 366 patients with NSCLC and other solid tumors enrolled in KRYSTAL-1 and KRYSTAL-12 (NCT04685135), respectively.
Among 366 patients who received adagrasib, 39% of patients were exposed for 6 months or longer and 12% were exposed for greater than one year. In this pooled safety population, the most common (≥ 25%) adverse reactions were nausea (70%), diarrhea (69%), vomiting (57%), fatigue (55%), musculoskeletal pain (38%), hepatotoxicity (37%), renal impairment (33%), edema (30%), dyspnea (26%), and decreased appetite (29%). In this pooled safety population, the most common Grade 3 or 4 (≥ 2%) laboratory abnormalities were decreased lymphocytes (20%), decreased hemoglobin (7%), increased alanine aminotransferase (4.5%), increased aspartate aminotransferase (4.2%), hypokalemia (3.6%), hyponatremia (3.4%), increased lipase (2.5%), decreased leukocytes (2.5%), decreased neutrophils (2.3%), and increased alkaline phosphatase (2.0%).
The data described in WARNINGS AND PRECAUTIONS and below also reflects exposure to adagrasib in combination with cetuximab in 94 patients with KRAS G12C-mutated, locally advanced or metastatic CRC in KRYSTAL-1. Non-Small Cell Lung Cancer The safety of adagrasib was evaluated in patients with KRAS G12C-mutated, locally advanced or metastatic NSCLC in KRYSTAL-1 [see Clinical Studies (14.1) ] . Patients received adagrasib 600 mg orally twice daily (n = 116).
Among patients who received adagrasib, 45% were exposed for 6 months or longer and 4% were exposed for greater than one year. The median age of patients who received adagrasib was 64 years (range 25 to 89), 56% female, 84% White, 8% Black or African American, and 4.3% Asian. Serious adverse reactions occurred in 57% of patients who received adagrasib.
Serious adverse reactions in ≥ 2% of patients were pneumonia (17%), dyspnea (9%), renal impairment (8%), sepsis (5%), hypoxia (4.3%), pleural effusion (4.3%), respiratory failure (4.3%), anemia (3.4%), cardiac fa… [Excerpted — this section continues on DailyMed.]
🔄 Drug Interactions ▾
7 DRUG INTERACTIONS See full prescribing information for clinically significant drug interactions with KRAZATI. ( 7 ) • Strong CYP3A4 Inducers : Avoid concomitant use. ( 7.1 ) • Strong CYP3A4 Inhibitors : Avoid concomitant use until adagrasib concentrations have reached steady state.
( 7.1 ) • Sensitive CYP3A4 Substrates : Avoid concomitant use with sensitive CYP3A4 substrates. ( 7.2 ) • Sensitive CYP2C9 or CYP2D6 Substrates or P-gp Substrates : Avoid concomitant use with sensitive CYP2C9 or CYP2D6 substrates or P-gp substrates where minimal concentration changes may lead to serious adverse reactions. ( 7.2 ) • Drugs That Prolong QT Interval : Avoid concomitant use with KRAZATI.
( 7.3 )
7.1Effects of Other Drugs on KRAZATI Strong CYP3A4 Inducers Avoid concomitant use of KRAZATI with strong CYP3A inducers. Adagrasib is a CYP3A4 substrate. Concomitant use of KRAZATI with a strong CYP3A inducer reduces adagrasib exposure [see Clinical Pharmacology (12.3) ] , which may reduce the effectiveness of KRAZATI.
Strong CYP3A4 Inhibitors Avoid concomitant use of KRAZATI with strong CYP3A inhibitors until adagrasib concentrations have reached steady state (after approximately 8 days). Adagrasib is a CYP3A4 substrate. If adagrasib concentrations have not reached steady state, concomitant use of a strong CYP3A inhibitor will increase adagrasib concentrations, [see Clinical Pharmacology (12.3) ], which may increase the risk of KRAZATI adverse reactions.
7.2Effects of KRAZATI on Other Drugs Sensitive CYP3A Substrates Avoid concomitant use of KRAZATI with sensitive CYP3A substrates unless otherwise recommended in the Prescribing Information for these substrates. Adagrasib is a CYP3A inhibitor. Concomitant use with KRAZATI increases exposure of CYP3A substrates [see Clinical Pharmacology (12.3) ] , which may increase the risk of adverse reactions related to these substrates.
Sensitive CYP2C9 Substrates Avoid concomitant use of KRAZATI with sensitive CYP2C9 substrates where minimal concentration changes may lead to serious adverse reactions unless otherwise recommended in the Prescribing Information for these substrates. Adagrasib is a CYP2C9 inhibitor. Concomitant use with KRAZATI increases exposure of CYP2C9 substrates [see Clinical Pharmacology (12.3) ] , which may increase the risk of adverse reactions related to these substrates.
Sensitive CYP2D6 Substrates Avoid concomitant use of KRAZATI with sensitive CYP2D6 substrates where minimal concentration changes may lead to serious adverse reactions unless otherwise recommended in the Prescribing Information for these substrates. Adagrasib is a CYP2D6 inhibitor. Concomitant use with KRAZATI increases exposure of CYP2D6 substrates [see Clinical Pharmacology (12.3) ] , which may increase the risk of adverse reactions related to these substrates.
P-gp Substrates Avoid concomitant use of KRAZATI with P-gp substrates where minimal concentration changes 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 KRAZATI increases exposure of P-gp substrates [see Clinical Pharmacology (12.3) ] , which may increase the risk of adverse reactions related to these substrates.
7.3Drugs That Prolong QTc Interval Avoid concomitant use of KRAZATI with other product(s) with a known potential to prolong the QTc interval. If concomitant use cannot be avoided, monitor electrocardiogram and electrolytes prior to starting KRAZATI, during concomitant use, and as clinically indicated [see Warnings and Precautions (5.2) ]. Withhold KRAZATI if the QTc interval is > 500 ms or the change from baseline is > 60 ms [see Dosage and Administration (2.3) ].
Adagrasib causes QTc interval prolongation [see Clinical Pharmacology (12.2) ]. Concomitant use of KRAZATI with other products that prolong the QTc interval may result in a greater increase in the QTc interval and adverse reactions associated with QTc interval pr… [Excerpted — this section continues on DailyMed.]
👥 Use in Specific Populations ▾
8 USE IN SPECIFIC POPULATIONS Lactation : Advise not to breastfeed. ( 8.2 )
8.1Pregnancy Risk Summary There are no available data on the use of KRAZATI in pregnant women. In animal reproduction studies, oral administration of adagrasib to pregnant rats and rabbits during the period of organogenesis did not cause adverse development effects or embryo-fetal lethality at exposures below the human exposure at the recommended dose of 600 mg twice daily (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 a rat embryo-fetal development study, once daily oral administration of adagrasib to pregnant rats during the period of organogenesis resulted in maternal toxicity (reduced body weight and food intake, and adverse clinical signs leading to moribund condition and early termination) and lower fetal body weight at 270 mg/kg dose level (approximately 2 times the recommended dose of 600 mg twice daily based on body surface area [BSA]). Adagrasib induced skeletal malformations, such as bent limbs, and skeletal variations, such as bent scapula, wavy ribs, and supernumerary short cervical ribs at 270 mg/kg, which were secondary to maternal toxicity and reduced fetal body weight.
In a rabbit embryo-fetal development study, once daily oral administration of adagrasib during the period of organogenesis resulted in lower fetal body weight and increased litter frequency of unossified sternebra at 30 mg/kg (approximately 0.11 times the human exposure based on area under the curve [AUC] at the clinical dose of 600 mg twice daily). This skeletal variation was associated with maternal toxicities, including reduced mean body weight and decreased food consumption. Adagrasib exposure did not cause adverse developmental effects and did not affect embryo-fetal survival in rabbits at doses up to 30 mg/kg once daily.
8.2Lactation Risk Summary There are no data on the presence of adagrasib or its metabolites in human milk, the effects on the breastfed child, or on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with KRAZATI and for 1 week after the last dose.
8.3Females and Males of Reproductive Potential Infertility Based on findings from animal studies, KRAZATI may impair fertility in females and males of reproductive potential [see Nonclinical Toxicology (13.1) ] .
8.4Pediatric Use The safety and effectiveness of KRAZATI has not been established in pediatric patients.
8.5Geriatric Use Of 116 patients with metastatic NSCLC who received adagrasib 600 mg orally twice daily in KRYSTAL-1, 49% (57 patients) were ≥ 65 years of age and 13% (15 patients) were ≥ 75 years of age. No overall differences in safety or effectiveness were observed between older and younger patients. Of 94 patients with metastatic CRC who received adagrasib 600 mg orally twice daily in combination with cetuximab in KRISTAL-1, 33% (31 patients) were ≥ 65 years of age and 2.1% (2 patients) were ≥ 75 years of age.
No overall differences in safety or effectiveness were observed between older and younger patients.
🤰 Pregnancy ▾
8.1Pregnancy Risk Summary There are no available data on the use of KRAZATI in pregnant women. In animal reproduction studies, oral administration of adagrasib to pregnant rats and rabbits during the period of organogenesis did not cause adverse development effects or embryo-fetal lethality at exposures below the human exposure at the recommended dose of 600 mg twice daily (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 a rat embryo-fetal development study, once daily oral administration of adagrasib to pregnant rats during the period of organogenesis resulted in maternal toxicity (reduced body weight and food intake, and adverse clinical signs leading to moribund condition and early termination) and lower fetal body weight at 270 mg/kg dose level (approximately 2 times the recommended dose of 600 mg twice daily based on body surface area [BSA]). Adagrasib induced skeletal malformations, such as bent limbs, and skeletal variations, such as bent scapula, wavy ribs, and supernumerary short cervical ribs at 270 mg/kg, which were secondary to maternal toxicity and reduced fetal body weight.
In a rabbit embryo-fetal development study, once daily oral administration of adagrasib during the period of organogenesis resulted in lower fetal body weight and increased litter frequency of unossified sternebra at 30 mg/kg (approximately 0.11 times the human exposure based on area under the curve [AUC] at the clinical dose of 600 mg twice daily). This skeletal variation was associated with maternal toxicities, including reduced mean body weight and decreased food consumption. Adagrasib exposure did not cause adverse developmental effects and did not affect embryo-fetal survival in rabbits at doses up to 30 mg/kg once daily.
🧒 Pediatric Use ▾
8.4Pediatric Use The safety and effectiveness of KRAZATI has not been established in pediatric patients.
🧓 Geriatric Use ▾
8.5Geriatric Use Of 116 patients with metastatic NSCLC who received adagrasib 600 mg orally twice daily in KRYSTAL-1, 49% (57 patients) were ≥ 65 years of age and 13% (15 patients) were ≥ 75 years of age. No overall differences in safety or effectiveness were observed between older and younger patients. Of 94 patients with metastatic CRC who received adagrasib 600 mg orally twice daily in combination with cetuximab in KRISTAL-1, 33% (31 patients) were ≥ 65 years of age and 2.1% (2 patients) were ≥ 75 years of age.
No overall differences in safety or effectiveness were observed between older and younger patients.
🧬 Clinical Pharmacology ▾
12 CLINICAL PHARMACOLOGY
12.1Mechanism of Action Adagrasib is an irreversible inhibitor of KRAS G12C that covalently binds to the mutant cysteine in KRAS G12C and locks the mutant KRAS protein in its inactive state that prevents downstream signaling without affecting wild-type KRAS protein. Adagrasib inhibited tumor cell growth and viability in cells harboring KRAS G12C mutations and resulted in tumor regression in KRAS G12C-mutated tumor xenograft models with minimal off-target activity. Adagrasib in combination with cetuximab had increased antitumor activity in some cell line-derived and patient-derived KRAS G12C-mutant CRC tumor xenograft models compared to adagrasib or cetuximab alone.
12.2Pharmacodynamics Adagrasib exposure-response relationships and the time course of pharmacodynamic response are unknown. Cardiac Electrophysiology Adagrasib increased QTc in a concentration-dependent manner. Based on the concentration-QTcF relationship, the mean (90% CI) QTcF change from baseline (ΔQTcF) was 18 (15, 21) ms at the mean steady-state maximum concentration (C max,ss ) in patients after administration of adagrasib 600 mg twice daily [see Warnings and Precautions (5.2) ].
12.3Pharmacokinetics The pharmacokinetics of adagrasib were studied in healthy subjects and in patients with KRAS G12C-mutated NSCLC or CRC. Adagrasib pharmacokinetic data are presented as mean (percent coefficient of variation) unless otherwise specified. Adagrasib AUC and C max increase dose proportionally over the dose range of 400 mg to 600 mg (0.67 to 1 times the approved recommended dose).
Adagrasib steady-state was reached within 8 days following administration of the approved recommended dosage and accumulation was approximately 6-fold. Absorption The median (min, max) T max of adagrasib is approximately 6 (6, 12) hours. Effect of Food No clinically significant differences in the pharmacokinetics of adagrasib were observed following administration of a high-fat and high-calorie meal (containing approximately 900 to 1000 calories, 50% from fat).
Distribution The apparent volume of distribution of adagrasib is 942 L (57%). Human plasma protein binding of adagrasib is approximately 98% in vitro. Elimination The adagrasib terminal elimination half-life is 23 hours (16%) and the apparent oral clearance (CL/F) is 37 L/h (54%) in patients.
Metabolism Adagrasib is metabolized primarily by CYP3A4 following single dose administration. Adagrasib inhibits its own CYP3A4 metabolism following multiple dosing to steady-state which permits CYP2C8, CYP1A2, CYP2B6, CYP2C9, and CYP2D6 to contribute to its metabolism at steady-state. Excretion Following a single oral dose of radiolabeled adagrasib, approximately 75% of the dose was recovered in feces (14% as unchanged) and 4.5% recovered in urine (2% as unchanged).
Specific Populations No clinically significant differences in the pharmacokinetics of adagrasib based on age (19 to 89 years), sex, race (White, Black or African American, or Asian), body weight (36 to 146 kg), ECOG PS (0, 1), tumor type (NSCLC or CRC), or tumor burden. No clinically significant differences in the pharmacokinetics of adagrasib are expected in patients with mild to severe renal impairment (CLcr 15 to < 90 mL/min estimated by Cockcroft-Gault equation) or in patients with mild to severe hepatic impairment (Child-Pugh classes A to C).
Drug Interaction Studies Clinical Studies and Model-Informed Approaches The following table describes the effect of other drugs on the pharmacokinetics of adagrasib. Table 7: Effect of Other Drugs on Adagrasib C max = maximum plasma concentration; AUC = area under the plasma concentration-time curve Concomitant Drug Adagrasib Dosage Changes in C max or AUC of Adagrasib C max % Decrease AUC % Decrease Rifampin (a strong CYP3A inducer) 600 mg single dose 88% 95% 600 mg multiple doses > 61% Predicted changes in C max or AUC of adagrasib. > 66% Strong CYP3A Inhibitors: Adagrasib C max increased by 2.4-fold and AUC incr… [Excerpted — this section continues on DailyMed.]
🧬 Mechanism of Action ▾
12.1Mechanism of Action Adagrasib is an irreversible inhibitor of KRAS G12C that covalently binds to the mutant cysteine in KRAS G12C and locks the mutant KRAS protein in its inactive state that prevents downstream signaling without affecting wild-type KRAS protein. Adagrasib inhibited tumor cell growth and viability in cells harboring KRAS G12C mutations and resulted in tumor regression in KRAS G12C-mutated tumor xenograft models with minimal off-target activity. Adagrasib in combination with cetuximab had increased antitumor activity in some cell line-derived and patient-derived KRAS G12C-mutant CRC tumor xenograft models compared to adagrasib or cetuximab alone.
📦 How Supplied / Storage and Handling ▾
16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied KRAZATI (adagrasib) tablets, 200 mg, oval shaped, white to off-white, immediate release, film coated tablets with "200" on one side and stylized "M" on the other side. KRAZATI (adagrasib) tablets are packaged in high-density polyethylene, white opaque, square bottles with desiccant and polypropylene, white, child resistant closures with a tamper-proof heat induction seal. NDC 80739-812-12: 200 mg, bottle containing 120 tablets.
NDC 80739-812-18: 200 mg, bottle containing 180 tablets. Storage and Handling Store tablets at room temperature, 20°C to 25°C (68°F to 77°F). Temperature excursions between 15°C and 30°C (59°F to 86°F) are permitted [see USP Controlled Room Temperature] .
📦 Storage and Handling ▾
Storage and Handling Store tablets at room temperature, 20°C to 25°C (68°F to 77°F). Temperature excursions between 15°C and 30°C (59°F to 86°F) are permitted [see USP Controlled Room Temperature] .
📋 Description ▾
11 DESCRIPTION Adagrasib is an irreversible inhibitor of KRAS G12C and belongs to the RAS GTPase family. The molecular formula is C 32 H 35 ClFN 7 O 2 and the 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-fluoroprop-2-enoyl)piperazin-2-yl}acetonitrile.
Adagrasib has the following chemical structure: Adagrasib is a crystalline solid. The solubility of adagrasib in the aqueous media decreases over the range pH 1.2 to 7.4 from > 262 mg/mL to < 0.010 mg/mL. KRAZATI (adagrasib) tablets for oral administration contain 200 mg of adagrasib.
The following are inactive ingredients: colloidal silicon dioxide, crospovidone, magnesium stearate (vegetable sourced), mannitol, and microcrystalline cellulose. The tablet film coating contains hypromellose, maltodextrin, medium chain triglycerides (vegetable sourced), polydextrose, talc, and titanium dioxide. Chemical Structure
💬 Information for Patients ▾
17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Gastrointestinal Adverse Reactions Advise patients that KRAZATI can cause severe gastrointestinal adverse reactions and to contact their healthcare provider for signs or symptoms of severe or persistent gastrointestinal adverse reactions [see Warnings and Precautions (5.1) ]. QTc Interval Prolongation Advise patients that KRAZATI can cause QTc interval prolongation and to contact their healthcare provider for signs or symptoms of arrhythmias [see Warnings and Precautions (5.2) ].
Hepatotoxicity Advise patients that KRAZATI can cause hepatotoxicity and to immediately contact their healthcare provider for signs or symptoms of liver dysfunction [see Warnings and Precautions (5.3) ] . Interstitial Lung Disease (ILD)/Pneumonitis Advise patients that KRAZATI can cause ILD / pneumonitis and to contact their healthcare provider immediately for new or worsening respiratory symptoms [see Warnings and Precautions (5.4) ]. Drug Interactions Advise patients to inform their healthcare providers of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products [see Drug Interactions (7.1) ] .
Missed Dose If a dose of KRAZATI is missed by greater than 4 hours, resume dosing at the next scheduled time [see Dosage and Administration (2.2) ]. Lactation Advise women not to breastfeed during treatment with KRAZATI and for 1 week after the last dose [see Use in Specific Populations (8.2) ]. Infertility Inform patients that KRAZATI may cause infertility [see Use in Specific Populations (8.3) ].
🧬 Pharmacokinetics ▾
12.3Pharmacokinetics The pharmacokinetics of adagrasib were studied in healthy subjects and in patients with KRAS G12C-mutated NSCLC or CRC. Adagrasib pharmacokinetic data are presented as mean (percent coefficient of variation) unless otherwise specified. Adagrasib AUC and C max increase dose proportionally over the dose range of 400 mg to 600 mg (0.67 to 1 times the approved recommended dose).
Adagrasib steady-state was reached within 8 days following administration of the approved recommended dosage and accumulation was approximately 6-fold. Absorption The median (min, max) T max of adagrasib is approximately 6 (6, 12) hours. Effect of Food No clinically significant differences in the pharmacokinetics of adagrasib were observed following administration of a high-fat and high-calorie meal (containing approximately 900 to 1000 calories, 50% from fat).
Distribution The apparent volume of distribution of adagrasib is 942 L (57%). Human plasma protein binding of adagrasib is approximately 98% in vitro. Elimination The adagrasib terminal elimination half-life is 23 hours (16%) and the apparent oral clearance (CL/F) is 37 L/h (54%) in patients.
Metabolism Adagrasib is metabolized primarily by CYP3A4 following single dose administration. Adagrasib inhibits its own CYP3A4 metabolism following multiple dosing to steady-state which permits CYP2C8, CYP1A2, CYP2B6, CYP2C9, and CYP2D6 to contribute to its metabolism at steady-state. Excretion Following a single oral dose of radiolabeled adagrasib, approximately 75% of the dose was recovered in feces (14% as unchanged) and 4.5% recovered in urine (2% as unchanged).
Specific Populations No clinically significant differences in the pharmacokinetics of adagrasib based on age (19 to 89 years), sex, race (White, Black or African American, or Asian), body weight (36 to 146 kg), ECOG PS (0, 1), tumor type (NSCLC or CRC), or tumor burden. No clinically significant differences in the pharmacokinetics of adagrasib are expected in patients with mild to severe renal impairment (CLcr 15 to < 90 mL/min estimated by Cockcroft-Gault equation) or in patients with mild to severe hepatic impairment (Child-Pugh classes A to C).
Drug Interaction Studies Clinical Studies and Model-Informed Approaches The following table describes the effect of other drugs on the pharmacokinetics of adagrasib. Table 7: Effect of Other Drugs on Adagrasib C max = maximum plasma concentration; AUC = area under the plasma concentration-time curve Concomitant Drug Adagrasib Dosage Changes in C max or AUC of Adagrasib C max % Decrease AUC % Decrease Rifampin (a strong CYP3A inducer) 600 mg single dose 88% 95% 600 mg multiple doses > 61% Predicted changes in C max or AUC of adagrasib. > 66% Strong CYP3A Inhibitors: Adagrasib C max increased by 2.4-fold and AUC increased by 4-fold following concomitant use of a single dose of 200 mg (0.33 times the approved recommended dose) with itraconazole (a strong CYP3A inhibitor).
No clinically significant differences in the pharmacokinetics of adagrasib at steady state were predicted when used concomitantly with itraconazole. No clinically significant differences in the pharmacokinetics of adagrasib were predicted or observed when used concomitantly with efavirenz (a moderate CYP3A inducer), pantoprazole (a proton pump inhibitor), rosuvastatin (a BCRP/OATP substrate), or eltrombopag (a BCRP inhibitor). The following table describes the effect of adagrasib on the pharmacokinetics of other drugs.
Table 8: Effect of Adagrasib on Other Drugs C max = maximum plasma concentration; AUC = area under the plasma concentration-time curve Concomitant Drug Adagrasib Dosage Fold Increase of Concomitant Drug C max AUC Midazolam (a sensitive CYP3A substrate) 400 mg 0.66 times the approved recommended dosage. twice daily 4.8-fold 21-fold 600 mg twice daily 3.1-fold Predicted changes in C max or AUC of concomitant drug. 31-fold Warfarin (a sensitive CYP2C9 substrate) 600 mg twice daily 1.1-fold 2.9-fold Dextrome… [Excerpted — this section continues on DailyMed.]
🧬 Pharmacodynamics ▾
12.2Pharmacodynamics Adagrasib exposure-response relationships and the time course of pharmacodynamic response are unknown. Cardiac Electrophysiology Adagrasib increased QTc in a concentration-dependent manner. Based on the concentration-QTcF relationship, the mean (90% CI) QTcF change from baseline (ΔQTcF) was 18 (15, 21) ms at the mean steady-state maximum concentration (C max,ss ) in patients after administration of adagrasib 600 mg twice daily [see Warnings and Precautions (5.2) ].
🔬 Clinical Studies ▾
14 CLINICAL STUDIES
14.1Non-Small Cell Lung Cancer The efficacy of adagrasib was evaluated in KRYSTAL-1 (NCT03785249), a multicenter, single-arm, open-label expansion cohort study. Eligible patients were required to have locally advanced or metastatic KRAS G12C-mutated NSCLC who previously received treatment with a platinum-based regimen and an immune checkpoint inhibitor, an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1, and at least one measurable lesion as defined by Response Evaluation criteria in Solid Tumors (RECIST v1.1).
Identification of a KRAS G12C mutation was prospectively determined by local testing using tissue specimens. Patients received adagrasib 600 mg orally twice daily until unacceptable toxicity or disease progression. Tumor assessments were performed every 6 weeks.
The major efficacy outcome measures were confirmed objective response rate (ORR) and duration of response (DOR) as evaluated by blinded independent central review (BICR) according to RECIST v1.1. In the efficacy population, KRAS G12C mutation status was determined by prospective local testing using tumor tissue specimens. Of the 112 patients with KRAS G12C mutation, tissue samples from 88% (98/112) patients were tested retrospectively using the QIAGEN therascreen KRAS RGQ PCR Kit.
While 89% (87/98) of patients were positive for KRAS G12C mutation, 11% (11/98) did not have a KRAS G12C mutation identified. In addition, plasma samples from 63% (71/112) patients were tested retrospectively using Agilent Resolution ctDx FIRST assay. While 66% (47/71) of patients were positive for KRAS G12C mutation, 34% (24/71) did not have a KRAS G12C mutation identified.
A total of 112 patients had at least one measurable lesion at baseline as assessed by BICR according to RECIST v1.1. The baseline demographic and disease characteristics in the efficacy population were: median age 64 years (range: 25 to 89), 55% female, 83% White, 8% were Black or African American, 4% Asian, 4% race not reported, 0.9% American Indian or Alaska Native, 16% Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 and 83% ECOG PS 1. Tumor histology was 97% adenocarcinoma and 89% of patients had metastatic disease.
Patients received a median of 2 prior systemic therapies (range 1 to 7); 43% received 1 prior line, 35% received 2 prior lines, 10% received 3 prior lines and 12% received 4 or more prior lines, 98% received both prior platinum and prior anti-PD-1/PD-L1 therapy. Sites of extra-thoracic disease included bone 42%, brain 30%, adrenals 21%, and liver 21%. Efficacy results are summarized in Table 9.
Table 9: Efficacy Results for KRYSTAL-1 CI = Confidence Interval Efficacy Parameter Adagrasib (n = 112) Objective Response Rate (95% CI) Assessed by BICR. 43 (34, 53) Complete response rate, %
0.9Partial response rate, % 42 Duration of Response Median Estimate using Kaplan-Meier method. in months (95% CI) 8.5 (6.2, 13.8) Patients with duration ≥ 6 months Observed proportion of patients with duration of response beyond landmark time. , % 58
14.2Colorectal Cancer The efficacy of adagrasib in combination with cetuximab was evaluated in KRYSTAL-1, a multicenter, single-arm, open-label expansion cohort study. Eligible patients were required to have locally advanced or metastatic KRAS G12C-mutated CRC and to have previously received therapy with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, a VEGF inhibitor if eligible, and an ECOG PS of 0 or 1. Patients initiated treatment with adagrasib 600 mg orally twice daily in combination with cetuximab administered either biweekly (77 patients with 500 mg/m 2 every two weeks) or weekly (17 patients with 400 mg/m 2 initial dose followed by 250 mg/m 2 weekly).
Treatment continued until unacceptable toxicity or disease progression. Tumor assessments were performed every 6 weeks. Adagrasib discontinuation required cetuximab discontinuation, however patients could continue to receive adagra… [Excerpted — this section continues on DailyMed.]
🧪 Nonclinical Toxicology ▾
13 NONCLINICAL TOXICOLOGY
13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies have not been conducted with adagrasib. Adagrasib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay and was not genotoxic in an in vitro chromosomal aberration assay or an in vivo micronucleus assay in rats. Fertility studies were not conducted with adagrasib.
In toxicology studies of up to 13-weeks in duration in rats, oral administration of adagrasib induced phospholipidosis which increased vacuolation in female reproductive organs, including vacuolation in ovaries (corpora lutea, macrophage or interstitial cells) and uterus (glandular epithelium), and atrophy with mucification of the vaginal mucosa at doses ≥ 150 mg/kg (approximately equal to or greater than the human exposure at the recommended dose based on area under the curve [AUC]). These findings reversed after cessation of dosing in the 28-day study but in the 13-week study, pigmented macrophage aggregates were observed in the ovaries of female rats after the recovery period.
In a 28-day repeat-dose toxicology study, oral administration of adagrasib to male rats induced atrophy and epithelial vacuolation of the prostate gland and seminal vesicles at 300 mg/kg (approximately 1.6 times the human exposure at the recommended dose based on AUC). These findings resolved after cessation of treatment.
13.2Animal Toxicology and/or Pharmacology Phospholipidosis (vacuolation and/or presence of foamy macrophages) was observed in multiple organs (e.g., lung, trachea, heart, skeletal, ovaries, uterus, adrenal gland, kidney, liver, lymph nodes, spleen, thymus, and thyroid in rats; and heart and lung in dogs) after repeated oral administration of adagrasib in rats and dogs. In toxicology studies of up to 13-week duration in rats, phospholipidosis was observed at doses ≥ 150 mg/kg (approximately ≥ 2 times the human exposure at the recommended dose based on AUC).
In a dog 28-day toxicity study, this effect was observed at 25 mg/kg (approximately equal to the human exposure at the recommended dose based on AUC). The extent of vacuolization and the presence of foamy macrophages were more prominent in the rat compared to dogs, and evidence of reversibility after cessation of treatment was noted for most organs. The significance of this finding in humans in unknown.
📄 Carcinogenesis, Mutagenesis, Impairment of Fertility ▾
13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies have not been conducted with adagrasib. Adagrasib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay and was not genotoxic in an in vitro chromosomal aberration assay or an in vivo micronucleus assay in rats. Fertility studies were not conducted with adagrasib.
In toxicology studies of up to 13-weeks in duration in rats, oral administration of adagrasib induced phospholipidosis which increased vacuolation in female reproductive organs, including vacuolation in ovaries (corpora lutea, macrophage or interstitial cells) and uterus (glandular epithelium), and atrophy with mucification of the vaginal mucosa at doses ≥ 150 mg/kg (approximately equal to or greater than the human exposure at the recommended dose based on area under the curve [AUC]). These findings reversed after cessation of dosing in the 28-day study but in the 13-week study, pigmented macrophage aggregates were observed in the ovaries of female rats after the recovery period.
In a 28-day repeat-dose toxicology study, oral administration of adagrasib to male rats induced atrophy and epithelial vacuolation of the prostate gland and seminal vesicles at 300 mg/kg (approximately 1.6 times the human exposure at the recommended dose based on AUC). These findings resolved after cessation of treatment.
📄 Patient Package Insert ▾
PATIENT INFORMATION KRAZATI ® (krah zah tee) (adagrasib) Tablets What is KRAZATI? KRAZATI is a prescription medicine used in adults: o alone to treat non-small cell lung cancer (NSCLC) o that has spread to other parts of the body or cannot be removed by surgery, and o whose tumor has an abnormal KRAS G12C gene, and o who have received at least one prior treatment. o in combination with a medicine called cetuximab to treat colon or rectal cancer (CRC) o that has spread to other parts of the body or cannot be removed by surgery, and o whose tumor has an abnormal KRAS G12C gene, and o who have previously received certain chemotherapy medicines.
Your healthcare provider will perform a test to make sure that KRAZATI is right for you. It is not known if KRAZATI is safe and effective in children. Before taking KRAZATI, tell your healthcare provider about all of your medical conditions, including if you: o have any heart problems, including heart failure and congenital long QT syndrome. o have liver problems. o are pregnant or plan to become pregnant.
It is not known if KRAZATI can harm your unborn baby. o are breastfeeding or plan to breastfeed. It is not known if KRAZATI passes into your breastmilk. Do not breastfeed during treatment and for 1 week after your last dose of KRAZATI.
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. KRAZATI can affect the way other medicines work, and other medicines can affect how KRAZATI works. How should I take KRAZATI? o Take KRAZATI exactly as your healthcare provider tells you to take it.
Do not change your dose or stop taking KRAZATI unless your healthcare provider tells you to. o Your healthcare provider may change your dose, or temporarily or permanently stop treatment with KRAZATI if you develop certain side effects. o For colon or rectal cancer, you will also receive cetuximab through a vein in your arm (intravenously) given by your healthcare provider. Your healthcare provider will permanently or temporarily stop your treatment with cetuximab if your treatment with KRAZATI is permanently or temporarily stopped. o Take your prescribed dose of KRAZATI 2 times each day, at about the same time each day. o Take KRAZATI either with food or without food. o Swallow KRAZATI tablets whole.
Do not chew, crush or split tablets. o If you vomit after taking a dose of KRAZATI, do not take an extra dose. Take your next dose at your next scheduled time. o If you miss a dose of KRAZATI, take the dose as soon as you remember. If it has been more than 4 hours, do not take the dose.
Take your next dose of KRAZATI at your next scheduled time. Do not take 2 doses at the same time to make up for a missed dose. What are possible side effects of KRAZATI?
KRAZATI can cause serious side effects, including: o Stomach and intestinal (gastrointestinal) problems. Stomach and intestinal side effects including nausea, diarrhea, or vomiting, are common with KRAZATI but can also sometimes be severe. KRAZATI can also cause serious stomach and intestinal side effects such as bleeding, obstruction, inflammation of the colon (colitis), and narrowing (stenosis). o Call your healthcare provider if you develop any of the signs or symptoms of stomach or intestinal problems listed above during treatment with KRAZATI . o Your healthcare provider may prescribe an antidiarrheal medicine or anti-nausea medicine, or other treatment, as needed. o Changes in the electrical activity of your heart called QTc prolongation.
Certain changes can occur in the electrical activity of your heart during treatment with KRAZATI and can be seen on a test called an electrocardiogram (ECG or EKG). QTc prolongation can increase your risk for irregular heartbeats that can be life-threatening, such as torsades de pointes, and can lead to sudden death. o You should not take KRAZATI if you have congenital long QT syndrome or if you currently have QTc prolongati… [Excerpted — this section continues on DailyMed.]
📄 Package Label / Principal Display Panel ▾
PRINCIPAL DISPLAY PANEL - 180 Tablet Bottle Carton NDC 80739-812-18 Rx Only KRAZATI ® (adagrasib tablets) 200 mg 180 tablets Bristol Myers Squibb ® PRINCIPAL DISPLAY PANEL - 180 Tablet Bottle Carton
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