Lonsurf

Trifluridine and tipiracil may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

• hair loss
• change in the way things taste
• loss of appetite
• mouth sores or swelling inside the mouth
• lack of energy
• excessive tiredness

Some side effects can be serious. If you experience any of these symptoms call your doctor immediately or get emergency medical treatment:

• fever, body aches, chills, or other signs of infection
• nausea, vomiting, diarrhea, or abdominal pain that is severe or does not go away
• weakness or shortness of breath when exercising
• pale skin
• chest pain
• pain with deep breathing
• coughing up blood
• unusual bleeding or bruising

Trifluridine and tipiracil may cause other side effects. Call your doctor if you have any unusual problems while taking this medication.

If you experience a serious side effect, you or your doctor may send a report to the Food and Drug Administration's (FDA) MedWatch Adverse Event Reporting program online (http://www.fda.gov/Safety/MedWatch) or by phone (1-800-332-1088).

Before and during your treatment with tipiracil and trifluridine, you will need blood tests. The timing of these tests is very important. Do not miss any scheduled appointments.

Follow all directions on your prescription label. Do not use this medicine in larger or smaller amounts or for longer than recommended.

Tipiracil and trifluridine works best if you take it within 1 hour after your morning and evening meals.

Tipiracil and trifluridine is given in a 28-day treatment cycle. You may need to use the medicine only on certain days of each cycle. Your doctor will determine how long to treat you with this medicine.

Wash your hands after handling tipiracil and trifluridine tablets.

Caregivers who touch or handle the tablets should wear rubber gloves.

To get the correct dose, you may need to take 2 or more tablets that are different strengths and colors. Follow your doctor's dosing instructions very carefully.

Tipiracil and trifluridine can lower blood cells that help your body fight infections and help your blood to clot. Your blood will need to be tested often. Your cancer treatments may be delayed based on the results of these tests.

Store tablets in their original container at room temperature, away from moisture and heat.

Do not put tipiracil and trifluridine tablets into a daily pill box. If you do not store this medicine in the original container, you will need to throw away any unused tablets after 30 days.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

LONSURF is indicated for the treatment of patients with metastatic colorectal cancer 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.

Lonsurf is part of the drug class:

• Pyrimidine analogues

Serious side effects have been reported with Lonsurf including the following:

• Bone marrow Suppression (Severe Myelosuppression): Contact your doctor right away if you notice signs or symptoms of infection. Your doctor will monitor your blood counts prior to and on Day 15 of each cycle. Keep all appointments for blood tests. If needed, your doctor may reduce dose and/or hold Lonsurf. 
• Gastrointestinal toxicity:  Contact your doctor right away if you experience severe or persistent nausea, vomiting, diarrhea, or abdominal pain.
• Low blood counts. Patients 65 years and older are at a higher risk of having low blood counts after taking Lonsurf. 
• Embryo-Fetal Toxicity: Lonsurf can cause fetal harm when administered to a pregnant woman. Females of reproductive potential are recommended to use effective contraception during treatment with Lonsurf. 

Lonsurf is available in two strengths and you may receive both strength tablets to provide the prescribed dose. Make sure to read your prescription labels carefully and take the appropriate number of tablets. 

Do not take Lonsurf if you are allergic to Lonsurf or to any of its ingredients.

Before taking Lonsurf, tell your doctor about all of your medical conditions. Especially tell your doctor if you:

• are allergic to Lonsurf or to any of its ingredients
• have liver problems
• have kidney problems
• have or ever had anemia (low red blood cells, neutropenia (low neutrophils) and thrombocytopenia (low platelets) 
• are pregnant or plan to become pregnant
• are breastfeeding or plan to breastfeed

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements.

• Store Lonsurf at 20°C to 25°C (68°F to 77°F).
• Lonsurf is a cytotoxic drug. Follow applicable special handling and disposal procedures.
• Keep this and all medicines out of the reach of children.
• If stored outside of original bottle, discard, following disposal procedures, after 30 days. 

None.

Colorectal Cancer

Study 1

The clinical efficacy and safety of Lonsurf were evaluated in an international, randomized, double-blind, placebo-controlled study conducted in patients with previously treated metastatic colorectal cancer (CRC).

A total of 800 patients were randomized 2:1 to receive Lonsurf (N=534) plus best supportive care (BSC) or matching placebo (N=266) plus BSC. Randomization was stratified by KRAS status (wild-type vs. mutant), time since diagnosis of first metastasis (<18 months vs. ≥ 18 months), and region (Japan vs. US, Europe and Australia). Key eligibility criteria included prior treatment with at least 2 lines of standard chemotherapy for metastatic CRC, ECOG 0-1, absence of brain metastasis, and absence of ascites requiring drainage in the past four weeks. Patients received 35 mg/m2 Lonsurf or matching placebo orally twice daily after meals on Days 1 - 5 and 8 – 12 of each 28-day cycle until disease progression or unacceptable toxicity. The major efficacy outcome measure was overall survival (OS) and an additional efficacy outcome measure was progression-free survival (PFS). The median age was 63 years, 61% were male, 58% and 35% were White and Asian respectively, and all patients had baseline ECOG Performance Status (PS) of 0 or 1. The primary site of disease was colon (62%) or rectum (38%). KRAS status was wild-type (49%) or mutant (51%) at study entry. All patients received prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. All but one patient received bevacizumab, and all but two patients with KRAS wild-type tumors received panitumumab or cetuximab. [see Dosage and Administration (2.1), Clinical Pharmacology (12.3)]

A statistically significant improvement in overall survival and progression-free survival were demonstrated in patients in the Lonsurf plus BSC arm compared to those who received placebo plus BSC (see Table 3 and Figure 1)

Figure 1 Kaplan-Meier Curves of Overall Survival

Lonsurf contains a combination of tipiracil and trifluridine. Tipiracil and trifluridine are anti-cancer medicines that interfer with the growth and spread of cancer cells in the body.

Lonsurf is used to treat colorectal cancer that has spread to other parts of the body (metastatic).

Lonsurf is usually given after other cancer medicines have been tried without success.

Before and during your treatment with Lonsurf, you will need blood tests.

Call your doctor at once if you develop signs of infection (fever, chills, body aches).

Follow all directions on your medicine label and package. Tell each of your healthcare providers about all your medical conditions, allergies, and all medicines you use.

Take Lonsurf exactly as prescribed by your doctor. Follow all directions on your prescription label. Do not use this medicine in larger or smaller amounts or for longer than recommended.

Before and during your treatment with Lonsurf, you will need blood tests. The timing of these tests is very important. Do not miss any scheduled appointments.

Lonsurf should be taken within 1 hour after your morning and evening meals.

Lonsurf is given in a 28-day treatment cycle. You may need to use the medicine only on certain days of each cycle. Your doctor will determine how long to treat you with this medicine.

Wash your hands after handling the tablets.

Caregivers who touch or handle the tablets should wear rubber gloves.

To get the correct dose, you may need to take 2 or more tablets that are different strengths and colors. Follow your doctor's dosing instructions very carefully.

Lonsurf can lower blood cells that help your body fight infections and help your blood to clot. Your blood will need to be tested often. Your cancer treatments may be delayed based on the results of these tests.

Store tablets in their original container at room temperature, away from moisture and heat.

Do not put the tablets into a daily pill box. If you do not store this medicine in the original container, you will need to throw away any unused tablets after 30 days.

Common side effects of Lonsurf include: infection, anemia, asthenia, diarrhea, fatigue, fever, nausea, neutropenia, thrombocytopenia, vomiting, and decreased appetite. Other side effects include: alopecia, and dysgeusia. See below for a comprehensive list of adverse effects.

Applies to tipiracil / trifluridine: oral tablet

Hematologic

Very common (10% or more): Anemia (77%), neutropenia (67%), thrombocytopenia (42%)
Common (1% to 10%): Febrile neutropenia[Ref]

Other

Very common (10% or more): Asthenia/fatigue (52%), infections (27%), pyrexia (19%)[Ref]

Gastrointestinal

Very common (10% or more): Nausea (48%), diarrhea (32%), vomiting (28%), abdominal pain (21%)
Common (1% to 10%): Stomatitis (8%)[Ref]

General

3.6% of patients discontinued treatment for an adverse event; 13.7% required a dose reduction, most commonly for neutropenia, anemia, febrile neutropenia, fatigue, and diarrhea.[Ref]

Respiratory

Common (1% to 10%): Nasopharyngitis, pulmonary emboli
Uncommon (0.1% to 1%): Interstitial lung disease[Ref]

Metabolic

Very common (10% or more): Decreased appetite (39%)[Ref]

Cardiovascular

Common (1% to 10%): QTc interval prolongation[Ref]

Nervous system

Common (1% to 10%): Dysgeusia[Ref]

Genitourinary

Common (1% to 10%): Urinary tract infections[Ref]

Dermatologic

Common (1% to 10%): Alopecia[Ref]

Some side effects of Lonsurf may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.