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KRAZATI is a brand name for Adagrasib. The medicine, its uses, side effects and dosage are the same regardless of brand.
Used for: 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…
Verbatim from this product's FDA label. Tap a section to expand.
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 ) • Swallow tablets whole with or without food. 1) ] . If no mutation is detected in a plasma specimen, test tumor tissue.
2) ] . 2 Recommended 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. 2) ] . 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. 3 Dosage 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.
2) ] . The recommended dosage modifications for adverse reactions are provided in Table 2. 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.
1) ] Grade 3 or 4 • Withhold KRAZATI until recovery to ≤ Grade 1 or return to baseline. • Resume KRAZATI at the next lower dose level. 1) ] Grade 3 or 4 • Withhold KRAZATI until recovery to ≤ Grade 1 or return to baseline. • Resume KRAZATI at the next lower dose level.
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.
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.
gov/medwatch . 1 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 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%).
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. 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 ) • 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. 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. 1 Gastrointestinal Adverse Reactions KRAZATI can cause severe gastrointestinal adverse reactions.
3%. In addition, nausea, diarrhea, or vomiting occurred in 89% of 366 patients, including 9% Grade 3. 3%. 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. 3) ]. , torsades de pointes) or sudden death . 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.
4 CONTRAINDICATIONS None. None. ( 4 )
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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. 3) ] Grade 2 AST or ALT • Decrease KRAZATI to the next lower dose level.
Grade 3 or 4 AST or ALT • Withhold KRAZATI until recovery to ≤ Grade 1 or return to baseline. • Resume KRAZATI at the next lower dose level. 4) ] Any Grade • Withhold KRAZATI if ILD/pneumonitis is suspected. 1) ] Grade 3 or 4 • Withhold KRAZATI until ≤ Grade 1 or return to baseline.
• Resume KRAZATI at the next lower dose level.
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. 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. 3% Asian. Serious adverse reactions occurred in 57% of patients who received adagrasib. 6%). 9%). Permanent discontinuation of adagrasib due to an adverse reaction occurred in 13% of patients.
9%) were cerebrovascular accident, dyspnea, decreased ejection fraction, encephalitis, gastrointestinal obstruction, hemorrhage, hepatotoxicity, hypotension, muscular weakness, pulmonary embolism, pyrexia, respiratory failure and sepsis.
Dose interruptions of adagrasib due to an adverse reaction occurred in 77% of patients. Adverse reactions requiring dosage interruption in ≥ 2% of patients who received adagrasib included nausea, hepatotoxicity, fatigue, vomiting, pneumonia, renal impairment, diarrhea, QTc interval prolongation, anemia, dyspnea, increased lipase, decreased appetite, dizziness, hyponatremia, muscular weakness, increased amylase, pneumonitis, sepsis and decreased weight.
Dose reductions of adagrasib due to an adverse reaction occurred in 28% of patients. Adverse reactions which required dose reductions in ≥ 2% of patients who received adagrasib included hepatotoxicity, fatigue, nausea, diarrhea, vomiting, and renal impairment.
The most common adverse reactions (≥ 20%) were diarrhea, nausea, fatigue, vomiting, musculoskeletal pain, hepatotoxicity, renal impairment, dyspnea, edema, decreased appetite, cough, pneumonia, dizziness, constipation, abdominal pain, and QTc interval prolongation.
The most common laboratory abnormalities (≥ 25%) were decreased lymphocytes, increased aspartate aminotransferase, decreased sodium, decreased hemoglobin, increased creatinine, decreased albumin, increased alanine aminotransferase, increased lipase, decreased platelets, decreased magnesium, and decreased potassium.
Table 3 summarizes the adverse reactions in KRYSTAL-1.
Table 3:
Adverse Reactions (≥ 20%) in Patients with KRAS G12C-mutated NSCLC Who Received Adagrasib in KRYSTAL-1 Adverse Reaction Adagrasib N = 116 All Grades (%) Grade 3 or 4 (%) Gastrointestinal Disorders Diarrhea Grouped term. 9 Constipation 22 0 Abdominal pain 21 0 General Disorders and Administration Site Conditions Fatigue 59 7 Edema 32 0 Musculoskeletal and Connective Tissue Disorders Musculoskeletal pain 41 7 Hepatobiliary Disorders Hepatotoxicity , Hepatotoxicity includes mixed liver injury, blood alkaline phosphatase increased, alanine aminotransferase increased, aspartate aminotransferase increased, liver function test increased, blood bilirubin increased, and bilirubin conjugated increased.
37 10 Renal and Urinary Disorders Renal impairment , Renal impairment includes acute kidney injury and increased blood creatinine. 9 Cardiac Disorders Electrocardiogram QT prolonged 20 6 Table 4 summarizes the laboratory abnormalities in KRYSTAL-1.
Table 4:
Select Laboratory Abnormalities Occurring (≥ 25%) That Worsened from Baseline in Patients with KRAS G12C-mutated NSCLC Who Received Adagrasib in KRYSTAL-1 Laboratory Abnormality Adagrasib Denominator used to calculate the rate varied from 106 to 113 based on the number of patients with a baseline value and at least one post-treatment value.
2) ] . Patients started treatment with adagrasib 600 mg twice daily in combination with cetuximab weekly (n = 17) or every two weeks (n = 77) . Among patients who received adagrasib in combination with cetuximab, 60% were exposed for greater than 6 months and 12% were exposed for greater than 12 months.
Serious adverse reactions occurred in 30% of patients who received adagrasib in combination with cetuximab. 1% each). A fatal adverse reaction of pneumonia occurred in 1 patient who received adagrasib in combination with cetuximab. Adverse reactions leading to discontinuation of adagrasib occurred in 2 patients.
Adverse reactions which resulted in permanent discontinuation of adagrasib (1 patient each) included abdominal pain and prolonged QT interval. Adverse reactions leading to dose interruptions of adagrasib occurred in 62% of patients.
The most common adverse reactions or laboratory abnormalities leading to dose interruption in ≥ 2% of patients who received adagrasib included diarrhea, nausea, vomiting, abdominal pain, dizziness, headache, pneumonia, alanine aminotransferase increased, aspartate aminotransferase increased, dyspnea, fatigue, pleural effusion, rash, anemia, electrocardiogram QT prolongation, blood bilirubin increased, blood creatinine increased, decreased appetite, dehydration, hemorrhage, hypomagnesemia, lipase increased, muscular weakness, musculoskeletal pain, and pyrexia.
Adverse reactions leading to dose reductions of adagrasib occurred in 35% of patients. The most common adverse reactions or laboratory abnormalities leading to dose reductions in ≥ 2% of patients who received adagrasib included fatigue, increased aspartate aminotransferase, increased alanine aminotransferase, nausea, decreased appetite, electrocardiogram QT prolongation, dizziness, acute kidney injury, diarrhea, dysarthria, and vomiting.
The most common adverse reactions (≥ 20%) were rash, nausea, diarrhea, vomiting, fatigue, musculoskeletal pain, hepatotoxicity, headache, dry skin, abdominal pain, decreased appetite, edema, anemia, dizziness, cough, constipation, and peripheral neuropathy.
The most common laboratory abnormalities (≥ 25%) were decreased lymphocytes, decreased hemoglobin, decreased leukocytes, increased alanine aminotransferase, decreased magnesium, decreased albumin, increased lipase, decreased potassium, increased aspartate aminotransferase, increased creatinine, decreased sodium, decreased calcium, increased amylase, and increased alkaline phosphatase.
Table 5 summarizes the adverse reactions in patients with metastatic CRC in KRYSTAL-1. 0. Adagrasib in Combination with Cetuximab N = 94 All Grades (%) Grade 3 or 4 (%) Skin and subcutaneous tissue disorders Rash Grouped term; includes multiple related terms.
1 Metabolism and Nutrition Disorders Decreased appetite 30 0 Blood and lymphatic system disorders Anemia 27 7 Respiratory Cough 25 0 Other clinically relevant adverse reactions observed in less than 20% of patients were infusion related reactions (15%).
Table 6 summarizes the laboratory abnormalities in patients with metastatic CRC in KRYSTAL-1.
Table 6:
Selected Laboratory Abnormalities (≥ 25%) in Patients Who Received Adagrasib in Combination with Cetuximab in KRYSTAL-1 Laboratory Abnormality Adagrasib in Combination with Cetuximab The denominator used to calculate the rate varied from 82 to 92 based on the number of patients with a baseline value and at least one post-treatment value.
1
2) ] . 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. 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 patients who are unable to avoid concomitant medications that are known to prolong the QT interval.
Correct electrolyte abnormalities. 3) ] . 3 Hepatotoxicity KRAZATI can cause hepatotoxicity, which may lead to drug-induced liver injury and hepatitis. 3% Grade 3. 5% were Grade 4. 1 to 48). Overall hepatotoxicity occurred in 37%, and 7% were Grade 3 or 4.
Hepatotoxicity leading to dose interruption or reduction occurred in 12% of patients. 5% of patients. 1% were Grade 4. 1 to 27). Overall hepatotoxicity occurred in 38%, and 10% were Grade 3 or 4. Hepatotoxicity leading to adagrasib dose interruption or reduction occurred in 12% of patients.
Monitor liver laboratory tests (AST, ALT, alkaline phosphatase and total bilirubin) prior to the start of KRAZATI and monthly for 3 months or as clinically indicated, with more frequent testing in patients who develop transaminase elevations.
1) ]. 4 Interstitial Lung Disease / Pneumonitis KRAZATI can cause interstitial lung disease (ILD)/pneumonitis, which can be fatal. 4% were Grade 3 or 4, and one case was fatal. The median time to first onset for ILD/pneumonitis was 12 weeks (range: 5 to 31 weeks).
8% of patients. 1% of patients. The time to first onset for ILD/pneumonitis was 38 weeks. , dyspnea, cough, fever) during treatment with KRAZATI. 3) ].