LONSURF SIDE EFFECTS
- Generic Name: trifluridine and tipiracil tablets
- Brand Name: Lonsurf
- Drug Class: Thymidine Phosphorylase Inhibitors
SIDE EFFECTS
The following clinically significant adverse reactions are described elsewhere in the labeling:
- Severe Myelosuppression
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 data in the WARNINGS AND PRECAUTIONS section and below reflect exposure to LONSURF at the recommended dose in 533 patients with metastatic colorectal cancer in RECOURSE and 335 patients with metastatic gastric cancer in TAGS. Among the 868 patients who received LONSURF, 11% were exposed for 6 months or longer and 1% were exposed for 12 months or longer. The most common adverse reactions or laboratory abnormalities . are anemia, neutropenia, fatigue/asthenia, nausea, thrombocytopenia, decreased appetite, diarrhea, vomiting, and pyrexia.
Metastatic Colorectal Cancer
The safety of LONSURF was evaluated in RECOURSE, a randomized (2:1), double-blind, placebo-controlled trial in patients with previously treated metastatic colorectal cancer. Patients received LONSURF 35 mg/m²/dose (n=533) or placebo (n=265) twice daily on Days 1 through 5 and Days 8 through 12 of each 28-day cycle. In RECOURSE, 12% of patients received LONSURF for more than 6 months and 1% of patients received LONSURF for more than 1 year.
The study population characteristics were: median age 63 years; 61% male; 57% White, 35% Asian, and 1% Black.
The most common adverse reactions or laboratory abnormalities (.10% in incidence) in patients treated with LONSURF at a rate that exceeds the rate in patients receiving placebo were anemia, neutropenia, asthenia/fatigue, nausea, thrombocytopenia, decreased appetite, diarrhea, vomiting, abdominal pain, and pyrexia.
In RECOURSE, 3.6% of patients discontinued LONSURF for an adverse reaction and 14% of patients required a dose reduction. The most common adverse reactions or laboratory abnormalities leading to dose reduction were neutropenia, anemia, febrile neutropenia, fatigue, and diarrhea.
Tables 1 and 2 list the adverse reactions and laboratory abnormalities (graded using CTCAE v4.03), respectively, observed in RECOURSE.
Table 1: Adverse Reactions (≥%) in Patients Receiving LONSURF and at a Higher Incidence (>2%) than in Patients Receiving Placebo in RECOURSE
| Adverse Reactions | LONSURF (N=533) |
Placebo (N=265) |
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| All Grades (%) | Grades 3-4* (%) | All Grades (%) | Grades 3-4* (%) | |
| General | ||||
| Asthenia/fatigue | 52 | 7 | 35 | 9 |
| Pyrexia | 19 | 1 | 14 | <1 |
| Gastrointestinal | ||||
| Nausea | 48 | 2 | 24 | 1 |
| Diarrhea | 32 | 3 | 12 | <1 |
| Vomiting | 28 | 2 | 14 | <1 |
| Abdominal pain | 21 | 2 | 18 | 4 |
| Stomatitis | 8 | <1 | 6 | 0 |
| Metabolism and nutrition | ||||
| Decreased appetite | 39 | 4 | 29 | 5 |
| Infections† | 27 | 6 | 16 | 5 |
| Nervous system | ||||
| Dysgeusia | 7 | 0 | 2 | 0 |
| Skin and subcutaneous tissue | ||||
| Alopecia | 7 | 0 | 1 | 0 |
| *No Grade 4 definition for nausea, abdominal pain, or fatigue in National Cancer Institute Common Terminology †Incidence reflects 64 preferred terms in the Infections and Infestations system organ class. |
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Table 2: Laboratory Abnormalities in RECOURSE
| Laboratory Parameter* | LONSURF | Placebo | ||
| All Grades (%) | Grades 3-4 (%) | All Grades (%) | Grades 3-4 (%) | |
| Hematologic | ||||
| Anemia† | 77 | 18 | 33 | 3 |
| Neutropenia | 67 | 38 | 1 | 0 |
| Thrombocytopenia | 42 | 5 | 8 | <1 |
| * Worst Grade at least one grade higher than baseline, with percentages based on number of patients with post-baseline samples, which may be <533 (LONSURF) or 265 (placebo) † One Grade 4 anemia adverse reaction based on clinical criteria was reported |
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In RECOURSE, pulmonary emboli occurred more frequently in LONSURF-treated patients (2%) compared to no patients on placebo.
Metastatic Gastric Cancer
The safety of LONSURF was evaluated in TAGS, an international, randomized (2:1), double-blind, placebo-controlled trial in patients with metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma who were previously treated with at least 2 prior chemotherapy regimens for advanced disease. Previous treatments must have included a fluoropyrimidine, a platinum, and either a taxane or irinotecan. Patients with HER2/neu-positive tumors must have received prior HER2/neu-targeted therapy, if available. Adjuvant chemotherapy could be counted as one prior regimen in patients who had recurrence during or within 6 months of completion of the adjuvant chemotherapy. Patients received LONSURF 35 mg/m²/dose (n=335) or placebo (n=168) twice daily on Days 1 through 5 and Days 8 through 12 of each 28-day cycle with best supportive care. In TAGS, 10% of patients received LONSURF for more than 6 months and 0.9% of patients received LONSURF for more than 1 year.
The study population characteristics were: median age 63 years (24 to 89 years); 73% male; 70% White, 16% Asian, and 1% Black.
The most common adverse reactions or laboratory abnormalitiles (≥10 in incidence ) in patients treated with LONSURF at a rate that exceeds the rate in patients receiving placebo were neutropenia, anemia, nausea, decreased appetite, thrombocytopenia, vomiting, and diarrhea.
In TAGS, 13% of patients discontinued LONSURF for an adverse reaction and 11% of patients required a dose reduction. The most common adverse reactions or laboratory abnormalities leading to dose reduction were neutropenia, anemia, febrile neutropenia, and diarrhea.
Tables 3 and 4 list the adverse reactions and laboratory abnormalities (graded using CTCAE v4.03), respectively, observed in TAGS.
Table 3: Adverse Reactions(≥5%) in Patients Receiving LONSURF and at a Higher Incidence (>2%) than in Patients Receiving Placebo in TAGS
| Adverse Reactions | LONSURF (N=335) |
Placebo (N=168) |
||
| All Grades (%) | Grades 3-4* (%) | All Grades (%) | Grades 3-4* (%) | |
| Gastrointestinal | ||||
| Nausea | 37 | 3 | 32 | 3 |
| Vomiting | 25 | 4 | 20 | 2 |
| Diarrhea | 23 | 3 | 14 | 2 |
| Metabolism and nutrition | ||||
| Decreased appetite | 34 | 9 | 31 | 7 |
| Infections† | 23 | 5 | 16 | 5 |
| *No Grade 4 definition for nausea or fatigue in NCI CTCAE, version 4.03. †Incidence reflects 46 preferred terms in the Infections and Infestations system organ class. |
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Table 4: Laboratory Abnormalities in TAGS
| Laboratory Parameter | LONSURF | Placebo | ||
| All Grades (%) | Grades 3-4 (%) | All Grades (%) | Grades 3-4 (%) | |
| Hematologic | ||||
| Neutropenia | 66 | 38 | 4 | 0 |
| Anemia† | 63 | 19 | 38 | 7 |
| Thrombocytopenia | 34 | 6 | 9 | 0 |
| * Worst Grade at least one Grade higher than baseline, with percent based on number of patients with post-baseline samples which may be <335 (LONSURF) or 168 (placebo) † Anemia: No Grade 4 definition in CTCAE, v4.03 |
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In TAGS, pulmonary emboli occurred more frequently in LONSURF-treated patients (3.1%) compared to 1.8% for patients on placebo.
Additional Clinical Experience
Interstitial lung disease was reported in 15 (0.2%) patients, 3 of which were fatal, among approximately 7,000 patients exposed to LONSURF in clinical studies and clinical practice settings in Asia.
SRC: NLM .