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Gavreto is a brand name for Pralsetinib. The medicine, its uses, side effects and dosage are the same regardless of brand.
Used for: 1 INDICATIONS AND USAGE GAVRETO is a kinase inhibitor indicated for treatment of: Adult patients with metastatic rearranged during transfection (RET ) fusion-positive non-small cell lung cancer as detected by an FDA approved test (NSCLC). ( 1.1 ) Adult and pediatric patients 12 years of age and older with advanced or…
Verbatim from this product's FDA label. Tap a section to expand.
2 DOSAGE AND ADMINISTRATION Select patients for treatment with GAVRETO based on the presence of a RET gene fusion. 1 , 14 ) The recommended dosage in adults and pediatric patients 12 years and older is 400 mg orally once daily on an empty stomach (no food intake for at least 2 hours before and at least 1 hour after taking GAVRETO).
1 Patient Selection Select patients for treatment with GAVRETO based on the presence of a RET gene fusion (NSCLC or thyroid cancer) [see Clinical Studies (14) ] . gov/CompanionDiagnostics. An FDA-approved test for the detection of RET gene fusion (thyroid cancer) is not currently available.
3) ] . Continue treatment until disease progression or until unacceptable toxicity. If a dose of GAVRETO is missed, it can be taken as soon as possible on the same day. Resume the regular daily dose schedule for GAVRETO the next day. Do not take an additional dose if vomiting occurs after GAVRETO but continue with the next dose as scheduled.
3 Dosage Modifications for Adverse Reactions The recommended dose reductions and dosage modifications for adverse reactions are provided in Table 1 and Table 2 .
Table 1:
Recommended Dose Reductions for GAVRETO for Adverse Reactions Dose Reduction Recommended Dosage First 300 mg once daily Second 200 mg once daily Third 100 mg once daily Permanently discontinue GAVRETO in patients who are unable to tolerate 100 mg taken orally once daily.
The recommended dosage modifications for adverse reactions are provided in Table 2 . 1) ] Grade 2 or 3 Withhold GAVRETO until resolution. Resume at a reduced dose ( Table 1 ). Grade 4 Permanently discontinue GAVRETO. 2) ] Grade 1 or 2 Withhold GAVRETO until resolution.
Resume by reducing the dose as shown in Table 1 . Permanently discontinue GAVRETO for recurrent ILD/pneumonitis. Grade 4 Permanently discontinue GAVRETO. 3) ] Grade 3 Withhold GAVRETO for Grade 3 hypertension that persists despite optimal antihypertensive therapy.
Resume at a reduced dose when hypertension is controlled. Grade 4 Discontinue GAVRETO. 4) ] Grade 3 or 4 Withhold GAVRETO and monitor AST/ALT once weekly until resolution to Grade 1 or baseline. Resume at reduced dose ( Table 1 ). For recurrent events at Grade 3 or higher, discontinue GAVRETO.
8) ] The most common adverse reactions (≥ 25%) were musculoskeletal pain, constipation, hypertension, diarrhea, fatigue, edema, pyrexia and cough. The most common Grade 3-4 laboratory abnormalities (≥ 2%) were decreased lymphocytes, decreased neutrophils, decreased hemoglobin, decreased phosphate, decreased leukocytes, decreased sodium, increased aspartate aminotransferase (AST), increased alanine aminotransferase (ALT), decreased calcium (corrected), decreased platelets, increased alkaline phosphatase, increased potassium, decreased potassium and increased bilirubin.
( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Rigel Pharmaceuticals, Inc. 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 in the WARNINGS AND PRECAUTIONS reflect exposure to GAVRETO as a single agent at 400 mg orally once daily in 540 patients in ARROW [see Clinical Studies (14) ]. Among 540 patients who received GAVRETO, 71% were exposed for 6 months or longer and 57% were exposed for greater than one year.
The most common adverse reactions (≥ 25%) were musculoskeletal pain, constipation, hypertension, diarrhea, fatigue, edema, pyrexia, and cough. The most common Grade 3-4 laboratory abnormalities (≥ 2%) were decreased lymphocytes, decreased neutrophils, decreased hemoglobin, decreased phosphate, decreased leukocytes, decreased sodium, increased aspartate aminotransferase (AST), increased alanine aminotransferase (ALT), decreased calcium (corrected), decreased platelets, increased alkaline phosphatase, increased potassium, decreased potassium and increased bilirubin.
In addition to the 540 patients, certain subsections in the WARNINGS AND PRECAUTIONS describe adverse reactions observed with exposure to GAVRETO as a single agent in a randomized, open-label study, AcceleRET-Lung (NCT04222972), which enrolled 223 patients with RET-fusion positive locally advanced unresectable or metastatic NSCLC.
5 WARNINGS AND PRECAUTIONS Serious Infections, Including Opportunistic Infections: Monitor for signs and symptoms of infection and treat appropriately. Withhold, reduce the dose, or permanently discontinue GAVRETO based on severity.
1 ) Interstitial Lung Disease (ILD)/Pneumonitis: Withhold GAVRETO for Grade 1 or 2 reactions until resolution and then resume at a reduced dose. Permanently discontinue for recurrent ILD/pneumonitis. Permanently discontinue for Grade 3 or 4 reactions.
2 ) Hypertension : Do not initiate GAVRETO in patients with uncontrolled hypertension. Optimize blood pressure (BP) prior to initiating GAVRETO. Monitor BP after 1 week, at least monthly thereafter and as clinically indicated. Withhold, reduce dose, or permanently discontinue GAVRETO based on severity.
3 ) Hepatotoxicity : Monitor ALT and AST prior to initiating GAVRETO, every 2 weeks during the first 3 months, then monthly thereafter and as clinically indicated. Withhold, reduce dose, or permanently discontinue GAVRETO based on severity.
4 ) Hemorrhagic Events : Permanently discontinue GAVRETO in patients with severe or life-threatening hemorrhage. 5 ) Tumor Lysis Syndrome: Closely monitor patients at risk and treat as clinically indicated. 6 ) Risk of Impaired Wound Healing: Withhold GAVRETO for at least 5 days prior to elective surgery.
Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of GAVRETO after resolution of wound healing complications has not been established. 7 ) Embryo-Fetal Toxicity : Can cause fetal harm.
Advise females of reproductive potential of the potential risk to a fetus and to use effective non-hormonal contraception. 1 Serious Infections, Including Opportunistic Infections GAVRETO may increase the risk for serious infections, including fatal and opportunistic infections.
4 CONTRAINDICATIONS None. None. ( 4 )
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5) ] Grade 3 or 4 Withhold GAVRETO until recovery to baseline or Grade 0 or 1. Discontinue GAVRETO for severe or life-threatening hemorrhagic events. 1) ] Grade 3 or 4 Withhold GAVRETO until improvement to ≤ Grade 2. Resume at reduced dose ( Table 1 ).
Permanently discontinue for recurrent Grade 4 adverse reactions. 4 Dose Modification for Use with CYP3A and/or P-glycoprotein (P-gp) Inhibitors Avoid coadministration of GAVRETO with any of the following: Strong CYP3A inhibitors Moderate CYP3A inhibitors P-gp inhibitors Combined P-gp and strong CYP3A inhibitors Combined P-gp and moderate CYP3A inhibitors If coadministration with any of the above inhibitors cannot be avoided, reduce the current dose of GAVRETO as recommended in Table 3 .
3) ] . 5 Dose Modification for Use with CYP3A Inducers Avoid coadministration of GAVRETO with any of the following: Strong CYP3A inducers Moderate CYP3A inducers If coadministration with any of the above inducers cannot be avoided, increase the starting dose of GAVRETO as recommended in Table 4 starting on Day 7 of coadministration of GAVRETO with the inducer.
3) ] .
Table 4:
Recommended Dosage Modifications for GAVRETO for Coadministration with CYP3A Inducers Current GAVRETO Dosage Recommended GAVRETO Dosage when Coadministered with: Strong CYP3A Inducers Moderate CYP3A Inducers 400 mg orally once daily 800 mg orally once daily 600 mg orally once daily 300 mg orally once daily 600 mg orally once daily 500 mg orally once daily 200 mg orally once daily 400 mg orally once daily 300 mg orally once daily
1) ]. Among the 281 patients who received GAVRETO, 72% were exposed for 6 months or longer and 56% were exposed for ≥1 year. The median age was 60 years (range: 26 to 87 years); 54% were female, 46% were White, 46% were Asian, and 4% were Hispanic/Latino.
Serious adverse reactions occurred in 65% of patients who received GAVRETO. The most frequent serious adverse reactions (in ≥ 2% of patients) were pneumonia, anemia, pneumonitis, pyrexia, sepsis, urinary tract infection, coronavirus infection, pleural effusion, dyspnea, musculoskeletal pain, pulmonary embolism, and seizure.
Fatal adverse reactions occurred in 7% of patients; fatal adverse reactions which occurred in > 1 patient included pneumonia (n=8), sepsis (n=3) and COVID (n=3). Permanent discontinuation due to an adverse reaction occurred in 20% of patients who received GAVRETO.
8%). Dosage interruptions due to an adverse reaction occurred in 73% of patients who received GAVRETO. Adverse reactions requiring dosage interruption in ≥ 2% of patients included anemia, pneumonia, pneumonitis, neutropenia, hypertension, increased blood creatine phosphokinase, fatigue, pyrexia, increased aspartate aminotransferase (AST), increased alanine aminotransferase (ALT), coronavirus infection, diarrhea, hypophosphatemia, musculoskeletal pain, thrombocytopenia, dyspnea, hemorrhage, leukopenia, lymphopenia, edema, sepsis, and vomiting.
Dose reductions due to adverse reactions occurred in 51% of patients who received GAVRETO. Adverse reactions requiring dosage reductions in ≥ 2% of patients included anemia, neutropenia, pneumonitis, increased blood creatine phosphokinase, leukopenia, hypertension, fatigue, pneumonia, and lymphopenia.
Table 5 summarizes the adverse reactions in patients with NSCLC in ARROW. 1 Skin and subcutaneous tissue disorders Rash Includes the preferred terms: Rash, Rash maculo-papular, Dermatitis acneiform, Erythema, Rash generalized, Rash papular, Rash macular, Rash erythematous 17 0 Clinically relevant adverse reactions occurring in < 15% of patients included pneumonitis (14%), vomiting (14%), abdominal pain (14%), and stomatitis (6%).
Table 6 summarizes the laboratory abnormalities in ARROW. 8 Hematology Decreased leukocytes 79 11 Decreased hemoglobin 78 18 Decreased lymphocytes 73 32 Decreased neutrophils 70 21 Decreased platelets 33 5 Clinically relevant laboratory abnormalities occurring in < 20% of patients who received GAVRETO included increased magnesium (14%).
2) ]. Among the 138 patients who received GAVRETO, 68% were exposed for 6 months or longer, and 40% were exposed for greater than one year. The median age was 59 years (range: 18 to 83 years); 36% were female, 74% were White, 17% were Asian, and 6% were Hispanic/Latino.
Serious adverse reactions occurred in 39% of patients who received GAVRETO. The most frequent serious adverse reactions (in ≥ 2% of patients) were pneumonia, pneumonitis, urinary tract infection, pyrexia, fatigue, diarrhea, dizziness, anemia, hyponatremia, and ascites.
2% of patients; fatal adverse reactions that occurred in > 1 patient included pneumonia (n=2). Permanent discontinuation due to an adverse reaction occurred in 9% of patients who received GAVRETO. Adverse reactions resulting in permanent discontinuation which occurred in > 1 patient included fatigue, pneumonia and anemia.
Dosage interruptions due to an adverse reaction occurred in 67% of patients who received GAVRETO. Adverse reactions requiring dosage interruption in ≥ 2% of patients included neutropenia, hypertension, diarrhea, fatigue, pneumonitis, anemia, increased blood creatine phosphokinase, pneumonia, urinary tract infection, musculoskeletal pain, vomiting, pyrexia, increased AST, dyspnea, hypocalcemia, cough, thrombocytopenia, abdominal pain, increased blood creatinine, dizziness, headache, decreased lymphocyte count, stomatitis, and syncope.
Dose reductions due to adverse reactions occurred in 44% of patients who received GAVRETO. Adverse reactions requiring dosage reductions in ≥ 2% of patients included neutropenia, anemia, hypertension, increased blood creatine phosphokinase, decreased lymphocyte count, pneumonitis, fatigue and thrombocytopenia.
Table 7 summarizes the adverse reactions occurring in RET -altered Thyroid Cancer Patients in ARROW. 7 Dysgeusia Dysgeusia includes ageusia, dysgeusia 17 0 Skin and Subcutaneous Rash Rash includes dermatitis, dermatitis acneiform, eczema, palmar-plantar, erythrodysaesthesia syndrome, rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pustular 24 0 Metabolism and Nutrition Decreased Appetite 15 0 Clinically relevant adverse reactions in < 15% of patients who received GAVRETO included tumor lysis syndrome and increased creatine phosphokinase.
Table 8 summarizes the laboratory abnormalities occurring in RET -altered Thyroid Cancer Patients in ARROW.
Table 8:
Select Laboratory Abnormalities (≥ 20%) Worsening from Baseline in RET-altered Thyroid Cancer Patients Who Received GAVRETO in ARROW Laboratory Abnormality GAVRETO N=138 Grades 1-4 (%) Grades 3-4 (%) Denominator for each laboratory parameter is based on the number of patients with a baseline and post-treatment laboratory value available, which ranged from 135 to 138 patients.
9 Clinically relevant laboratory abnormalities in patients who received GAVRETO included increased phosphate (40%). Other Clinical Trials Experience AcceleRET-Lung trial (NCT04222972) In AcceleRET-Lung trial (NCT04222972), single agent GAVRETO (n=108) was compared to chemotherapy/immunotherapy (n=104) in patients with RET fusion-positive NSCLC.
52%), including pneumonia (29% vs. 6%), urinary tract infection (22% vs. 8%), and opportunistic infections (20% vs. 6%). Opportunistic infections included pneumocystis jirovecii pneumonia, fungal infections, legionella pneumonia, cytomegalovirus infection, and herpes simplex.
7% with Grade 4, and 7% with fatal outcomes. Among the patients who received chemotherapy/immunotherapy, infections occurred in 52%, including 10% with Grade 3. Infections in the GAVRETO arm included pneumonia, urinary tract infection, opportunistic infections (such as pneumocystis jirovecii pneumonia, and fungal infections) and others.
Monitor patients for signs and symptoms of infection and treat appropriately. 3) ] . 2 Interstitial Lung Disease/Pneumonitis Severe, life-threatening, and fatal interstitial lung disease (ILD) / pneumonitis can occur in patients treated with GAVRETO.
2% with fatal reactions. Monitor for pulmonary symptoms indicative of ILD/pneumonitis. , dyspnea, cough, and fever). 3) ] . 1) ] . 8% had their dose reduced for hypertension. Treatment-emergent hypertension was most commonly managed with anti-hypertension medications.
Do not initiate GAVRETO in patients with uncontrolled hypertension. Optimize blood pressure prior to initiating GAVRETO. Monitor blood pressure after 1 week, at least monthly thereafter and as clinically indicated. Initiate or adjust anti-hypertensive therapy as appropriate.
3) ] . 5% of patients treated with GAVRETO. 1) ]. 7 years). Monitor AST and ALT prior to initiating GAVRETO, every 2 weeks during the first 3 months, then monthly thereafter and as clinically indicated. 3) ] . 5 Hemorrhagic Events Serious, including fatal, hemorrhagic events can occur with GAVRETO.
1% of patients treated with GAVRETO including one patient with a fatal hemorrhagic event. 3) ] . 1) ] . Patients may be at risk of TLS if they have rapidly growing tumors, a high tumor burden, renal dysfunction, or dehydration. Closely monitor patients at risk, consider appropriate prophylaxis including hydration, and treat as clinically indicated.
7 Risk of Impaired Wound Healing Impaired wound healing can occur in patients who receive drugs that inhibit the vascular endothelial growth factor (VEGF) signaling pathway. Therefore, GAVRETO has the potential to adversely affect wound healing.
Withhold GAVRETO for at least 5 days prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of GAVRETO after resolution of wound healing complications has not been established.
8 Embryo-Fetal Toxicity Based on findings from animal studies and its mechanism of action, GAVRETO can cause fetal harm when administered to a pregnant woman. Oral administration of pralsetinib to pregnant rats during the period of organogenesis resulted in malformations and embryolethality at maternal exposures below the human exposure at the clinical dose of 400 mg once daily.
Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with GAVRETO and for 2 weeks after the last dose. 3) ] .