Lonsurf

LONSURF is a combination of trifluridine, a nucleoside metabolic inhibitor, and tipiracil, a thymidine phosphorylase inhibitor, indicated for the treatment of adult patients with:

• metastatic colorectal cancer as a single agent or in combination with bevacizumab who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type, an anti-EGFR therapy. (
  1.1 Metastatic Colorectal Cancer

  LONSURF, as a single agent or in combination with bevacizumab, is indicated for the treatment of adult patients with metastatic colorectal cancer previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type, an anti-EGFR therapy.
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• metastatic gastric or gastroesophageal junction adenocarcinoma previously treated with at least two prior lines of chemotherapy that included a fluoropyrimidine, a platinum, either a taxane or irinotecan, and if appropriate, HER2/neu-targeted therapy. (
  1.2 Metastatic Gastric Cancer

  LONSURF is indicated for the treatment of adult patients with metastatic gastric or gastroesophageal junction adenocarcinoma previously treated with at least two prior lines of chemotherapy that included a fluoropyrimidine, a platinum, either a taxane or irinotecan, and if appropriate, HER2/neu-targeted therapy.
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• Recommended Dosage
  : 35 mg/m²/dose orally twice daily with food on Days 1 through 5 and Days 8 through 12 of each 28-day cycle. (
  2.1 Recommended Dosage

  The recommended dosage of LONSURF as a single agent or in combination with bevacizumab is 35 mg/m²up to a maximum of 80 mg per dose (based on the trifluridine component) orally twice daily with food on Days 1 through 5 and Days 8 through 12 of each 28-day cycle until disease progression or unacceptable toxicity. Round dose to the nearest 5 mg increment.

  Refer to the Prescribing Information for bevacizumab dosing information.

  Instruct patients to swallow LONSURF tablets whole.
  
  
  
  Instruct patients not to retake doses of LONSURF that are vomited or missed and to continue with the next scheduled dose.
  
  
  
  LONSURF is a cytotoxic drug. Follow applicable special handling and disposal procedures.¹
  
  
  
  Table 1shows the calculated initial daily dose based on body surface area (BSA).

  Table 1: Recommended Dosage According to Body Surface Area (BSA)

  BSA (m2)	Total daily dose (mg)	Dose (mg) administered twice daily	Tablets per dose
  			15 mg	20 mg
  < 1.07	70	35	1	1
  1.07 – 1.22	80	40	0	2
  1.23 – 1.37	90	45	3	0
  1.38 – 1.52	100	50	2	1
  1.53 – 1.68	110	55	1	2
  1.69 – 1.83	120	60	0	3
  1.84 – 1.98	130	65	3	1
  1.99 – 2.14	140	70	2	2
  2.15 – 2.29	150	75	1	3
  ≥2.30	160	80	0	4
  )

Tablets:

• 15 mg trifluridine/6.14 mg tipiracil: white, biconvex, round, film-coated, imprinted with ‘15’ on one side, and ‘102’ and ‘15 mg’ on the other side, in gray ink.
• 20 mg trifluridine/8.19 mg tipiracil: pale red, biconvex, round, film-coated, imprinted with ‘20’ on one side, and ‘102’ and ‘20 mg’ on the other side, in gray ink.

• Lactation
  : Advise not to breastfeed. (
  8.2 Lactation

  Risk Summary

  There are no data on the presence of trifluridine, tipiracil or its metabolites in human milk or its effects on the breastfed child or on milk production. In nursing rats, trifluridine and tipiracil or their metabolites were present in breast milk

  (see Data)

  . Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with LONSURF and for 1 day following the final dose.

  Data

  Radioactivity was excreted in the milk of nursing rats dosed with trifluridine/tipiracil containing¹⁴C-FTD or¹⁴C-tipiracil (TPI). Levels of FTD-derived radioactivity were as high as approximately 50% of the exposure in maternal plasma an hour after dosing with trifluridine/tipiracil and were approximately the same as those in maternal plasma for up to 12 hours following dosing. Exposure to TPI-derived radioactivity was higher in milk than in maternal plasma beginning 2 hours after dosing and continuing for at least 12 hours following administration of trifluridine/tipiracil.
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• Geriatric Use
  : For LONSURF as a single agent, Grade 3 or 4 neutropenia, Grade 3 anemia and Grade 3 or 4 thrombocytopenia occurred more commonly in patients 65 years or older. (
  8.5 Geriatric Use

  Of the 1114 patients with metastatic colorectal cancer or gastric cancer who received single agent LONSURF in clinical studies, 45% were 65 years of age or over, and 11% were 75 and over. In the 246 patients who received LONSURF in combination with bevacizumab; 41% were 65 years of age or over, and 10% were 75 and over. While these studies were not designed to detect a difference in efficacy, no overall differences were observed in patients 65 or older versus younger patients with either LONSURF as a single agent or LONSURF in combination with bevacizumab.

  Patients 65 years of age or older who received LONSURF as a single agent had a higher incidence of the following hematologic laboratory abnormalities compared to patients younger than 65 years: Grade 3 or 4 neutropenia (46% vs 32%), Grade 3 anemia (20% vs 14%), and Grade 3 or 4 thrombocytopenia (6% vs 3%). Patients 65 years of age or older who received LONSURF in combination with bevacizumab had a higher incidence of the following hematologic laboratory abnormalities compared to patients younger than 65 years: Grade 3 or 4 neutropenia (60% vs 46%) and Grade 3 or 4 thrombocytopenia (5% vs 4%).
  ) For LONSURF in combination with bevacizumab Grade 3 or 4 neutropenia and Grade 3 or 4 thrombocytopenia occurred more commonly in patients 65 years or older. (
  8.5 Geriatric Use

  Of the 1114 patients with metastatic colorectal cancer or gastric cancer who received single agent LONSURF in clinical studies, 45% were 65 years of age or over, and 11% were 75 and over. In the 246 patients who received LONSURF in combination with bevacizumab; 41% were 65 years of age or over, and 10% were 75 and over. While these studies were not designed to detect a difference in efficacy, no overall differences were observed in patients 65 or older versus younger patients with either LONSURF as a single agent or LONSURF in combination with bevacizumab.

  Patients 65 years of age or older who received LONSURF as a single agent had a higher incidence of the following hematologic laboratory abnormalities compared to patients younger than 65 years: Grade 3 or 4 neutropenia (46% vs 32%), Grade 3 anemia (20% vs 14%), and Grade 3 or 4 thrombocytopenia (6% vs 3%). Patients 65 years of age or older who received LONSURF in combination with bevacizumab had a higher incidence of the following hematologic laboratory abnormalities compared to patients younger than 65 years: Grade 3 or 4 neutropenia (60% vs 46%) and Grade 3 or 4 thrombocytopenia (5% vs 4%).
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• Hepatic Impairment
  : Do not initiate LONSURF in patients with baseline moderate or severe hepatic impairment. (
  8.7 Hepatic Impairment

  No adjustment to the starting dosage of LONSURF is recommended for patients with mild hepatic impairment. Do not initiate LONSURF in patients with baseline moderate or severe (total bilirubin >1.5 times ULN and any AST) hepatic impairment

  [see Clinical Pharmacology (12.3)]

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• Renal Impairment
  : Reduce LONSURF dose in patients with severe renal impairment. (
  8.6 Renal Impairment

  No dose adjustment is recommended for patients with mild or moderate renal impairment (CLcr of 30 to 89 mL/min as determined by the Cockcroft-Gault formula). Reduce the dose of LONSURF for patients with severe renal impairment (CLcr of 15 to 29 mL/min)

  [see Dosage and Administration (2.3)]

  . The pharmacokinetics of trifluridine and tipiracil have not been studied in patients with end stage renal disease.
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