Tevimbra Drug Information

Recommended Dosage

The recommended dosages of TEVIMBRA administered intravenously as a single agent or in combination with other therapeutic agents are presented in Table 1. Table 1: Recommended Dosages for TEVIMBRA as a Single Agent or in Combination with Other Therapeutic Agents Refer to the respective Prescribing Information for each therapeutic agent administered in combination with TEVIMBRA for the recommended dosage information, as appropriate.

Dosage Modifications for Adverse Reactions

No dose reduction of TEVIMBRA is recommended. In general, withhold TEVIMBRA for severe (Grade 3) immune-mediated adverse reactions. Permanently discontinue TEVIMBRA for life-threatening (Grade 4) immune-mediated adverse reactions, recurrent severe (Grade 3) immune-mediated reactions that require systemic immunosuppressive treatment, or an inability to reduce corticosteroid dose to 10 mg or less of prednisone equivalent per day within 12 weeks of initiating steroids.

Dosage modifications for TEVIMBRA for adverse reactions that require management different from these general guidelines are summarized in Table 2. Refer to the respective Prescribing Information for dosage modifications for the platinum and fluoropyrimidine agent administered in combination with TEVIMBRA. Table 2: Recommended

Preparation and Administration Preparation

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. TEVIMBRA is a clear to slightly opalescent, colorless to slightly yellow solution. Discard the vial if the solution is cloudy, discolored, or contains visible particles.

Do not shake the vial. Prepare the solution for infusion as follows: Withdraw the required volume of TEVIMBRA from the vial(s). Transfer solution into an intravenous infusion bag containing 0.9% Sodium Chloride Injection, USP to prepare an infusion solution with a final concentration of 2 mg/mL to 5 mg/mL.

Mix diluted solution by gentle inversion to avoid foaming or excessive shearing of the solution. Do not shake. TEVIMBRA is for single use only.

Discard any unused portion left in the vial. Storage of Diluted Solution This product does not contain any preservatives. If not used immediately, store the TEVIMBRA diluted solution either: At room temperature at 20°C to 25°C (68°F to 77°F) for up to 4 hours, including preparation and infusion duration.

Discard after 4 hours. Under refrigeration at 2°C to 8°C (36°F to 46°F) for up to 10 days (240 hours), including preparation and infusion duration. Allow the diluted solution to come to room temperature prior to administration.

Discard after 10 days (240 hours). Protect diluted solution from light during storage. Do not freeze the diluted solution.

Administration Administer diluted solution by intravenous infusion through an intravenous line with a sterile, nonpyrogenic, low protein binding 0.2 micron or 0.22 micron in-line or add-on filter. For 150 mg and 200 mg doses, administer the initial infusion over 60 minutes. If tolerated, all subsequent infusions may be administered over 30 minutes.

For 300 mg doses, administer the initial infusion over 90 minutes. If tolerated, administer the second infusion over 60 minutes. If the second infusion is tolerated, administer subsequent infusions over 30 minutes.

For 400 mg doses, administer the initial infusion over 120 minutes. Do NOT coadminister other drugs through the same infusion line. Do NOT administer TEVIMBRA as an intravenous push or single bolus injection.

Flush the intravenous line at the end of infusion.

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 WARNINGS AND PRECAUTIONS reflect exposure to TEVIMBRA as a single agent in 2390 patients enrolled in three randomized open-label, active-controlled studies (BGB-A317-301, RATIONALE-302, BGB-A317-303) and six open-label, single-arm studies BGB-A 7 patients with esophageal squamous cell carcinoma and 2083 patients with advanced or recurrent tumors. TEVIMBRA was administered at a dose of 200 mg intravenously once every 3 weeks, except in study BGB-A317_Study_001 where patients also received other dosage regimens.

First-line Treatment of Unresectable or Metastatic Esophageal Carcinoma (ESCC) The safety of TEVIMBRA in combination with chemotherapy was evaluated in RATIONALE-306, a randomized, placebo-controlled, multicenter, double-blind trial in patients with unresectable, advanced, or metastatic ESCC. The chemotherapy doublet regimens consisted of: Platinum (cisplatin or oxaliplatin ) and a fluoropyrimidine (5-FU or capecitabine ) or Platinum (cisplatin or oxaliplatin ) and (paclitaxel 175 mg/m 2 IV, on Day 1) Patients were treated until disease progression or unacceptable toxicity. The median duration of exposure was 6.4 months (range: 0.1 to 38.3 months) in TEVIMBRA-treated patients.

Serious adverse reactions occurred in 48% of patients receiving TEVIMBRA in combination with chemotherapy. Fatal adverse reactions occurred in 8% of patients who received TEVIMBRA in combination with chemotherapy. Permanent discontinuation of TEVIMBRA due to adverse reactions occurred in 13% of patients.

The adverse reaction which resulted in discontinuation in ≥2% of patients was pneumonitis (2.2%). Dosage interruptions of TEVIMBRA due to adverse reactions occurred in 52% of patients. Adverse reactions which required dosage interruption in ≥2% of patients were neutrophil count decreased (7%), fatigue (6%), pneumonia (6%), anemia ( %) adverse reactions including laboratory abnormalities were decreased neutrophil count, decreased sodium, increased glucose, anemia, fatigue, decreased appetite, increased AST, decreased potassium, increased serum creatinine, decreased calcium, increased ALT, diarrhea, stomatitis, and vomiting.

Adverse reactions and laboratory abnormalities are listed in Table 3 and Table 4, respectively. The trial excluded patients who had brain or leptomeningeal metastases that were symptomatic or required treatment, active autoimmune disease, a medical condition requiring systemic corticosteroids or immunosuppressants, or apparent tumor invasion of organs adjacent to the esophageal site. Serious adverse reactions occurred in 41% of patients; the most frequent serious adverse reactions (≥2%) were pneumonia, dysphagia, hemorrhage, pneumonitis (including pneumonitis and immune-mediated pneumonitis), and esophageal obstruction.

Fatal adverse reactions occurred in 7% of patients who received TEVIMBRA, including the following which occurred in more than one patient: pneumonia/pneumonitis (5 patients), hemorrhage (3 patients), and death due to an unknown cause (3 patients). Permanent discontinuation of TEVIMBRA due to an adverse reaction occurred in 19% of patients. Adverse reactions which resulted in permanent discontinuation in ≥1% of patients were hemorrhage, pneumonitis (including pneumonitis and immune-mediated pneumonitis), and pneumonia.

Dosage interruptions of TEVIMBRA due to an adverse reaction occurred in 23% of patients. Adverse reactions which required dosage interruptions in ≥2% of patients were pneumonia, pneumonitis, and fatigue. The most common (≥20%) adverse reactions were anemia, fatigue, musculoskeletal pain, decreased weight, and cough.

Adverse reactions and laboratory abnormalities are listed in Table 5 and Table 6, respectively. Table 5: Adverse Reactions (≥10%) in Patients With ESCC Receiving TEVIMBRA in RATIONALE- 3 Table 6: Laboratory Abnormalities Worsening From Baseline Occurring in ≥10% of Patients Receiving TEVIMBRA in RATIONALE- Treatment of Previously Untreated Unresectable or Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma (G/GEJ) The safety of TEVIMBRA in combination with chemotherapy was evaluated in RATIONALE-305, a randomized, multicenter, double-blind, placebo-controlled trial in patients with previously untreated unresectable or metastatic G/GEJ adenocarcinoma. The median duration of exposure was 5.91 months (range: 0.1 to 47 months) in TEVIMBRA-treated patients.

Adverse drug reactions which resulted in permanent discontinuation in ≥1% of patients were death, fatigue, and pneumonitis. Dosage interruption of TEVIMBRA due to an adverse drug reaction occurred in 49% of patients. The most common (≥20%) adverse reactions, including laboratory abnormalities, for TEVIMBRA in combination with chemotherapy were nausea, fatigue, decreased appetite, anemia, peripheral sensory neuropathy, vomiting, decreased platelet count, decreased neutrophil count, increased aspartate aminotransferase, diarrhea, abdominal pain, increased alanine aminotransferase, white blood cell count decreased, decreased weight, and pyrexia.

Adverse reactions and laboratory abnormalities are listed in Table 7 and Table 8, respectively. Table 7: Adverse Reactions (≥10%) in Patients with G/GEJ Receiving TEVIMBRA + Chemotherapy with a Difference Between Arms of ≥5% for All Grades or ≥2% for Grades 3 and 4 vs Placebo + Chemotherapy in RATIONALE-, infusion-related reaction, dyspnea, hepatitis, hyperthyroidism, pneumonitis, hyperglycemia, myalgia, diabetes mellitus, pancreatitis, arthritis, Sjogren's syndrome, thyroiditis, adrenal insufficiency, hypophysitis, myasthenia gravis, uveitis, myocarditis, pericarditis, colitis, vitiligo, myositis, and nephritis. Table 8: Select Laboratory Abnormalities Worsening from Baseline Occurring in ≥10% of Patients Receiving TEVIMBRA + Chemotherapy with a Difference Between Arms of ≥5% for All Grades or ≥2% for Grades 3 and 4 vs Placebo + Chemotherapy in RATIONALE- 9 Other Clinically Important Laboratory Abnormalities Occurring in <20% include: Creatinine increased, potassium increased, glucose decreased, sodium increased, lymphocytes increased, hemoglobin increased.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of TEVIMBRA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome, toxic epidermal necrolysis (including fatal cases).

Immune system disorders: Immune-mediated cystitis.

Pregnancy Risk Summary Based on its mechanism of action, TEVIMBRA can cause fetal harm when administered to a pregnant woman. There are no available data on the use of TEVIMBRA in pregnant women. Animal studies have demonstrated that inhibition of the PD-1/PD-L1 pathway can lead to increased risk of immune-mediated rejection of the developing fetus resulting in fetal death (see Data ).

Human IgG4 immunoglobulins (IgG4) are known to cross the placental barrier; therefore, tislelizumab-jsgr has the potential to be transmitted from the mother to the developing fetus. Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is respectively.

Data Animal Data Animal reproduction studies have not been conducted with TEVIMBRA to evaluate its effect on reproduction and fetal development. A central function of the PD-1/PD-L1 pathway is to preserve pregnancy by maintaining maternal immune tolerance to the fetus. In murine models of pregnancy, blockade of PD-L1 signaling has been shown to disrupt tolerance to the fetus and to result in an increase in fetal loss; therefore, potential risks of administering TEVIMBRA during pregnancy include increased rates of abortion or stillbirth.

As reported in the literature, there were no malformations related to the blockade of PD-1 signaling in the offspring of these animals; however, immune-mediated disorders occurred in PD-1 and PD-L1 knockout mice. Based on its mechanism of action, fetal exposure to tislelizumab-jsgr may increase the risk of developing immune-mediated disorders or altering the normal immune response.

Pediatric Use The safety and effectiveness of TEVIMBRA have not been established in pediatric patients.