Lymphir Drug Information

LYMPHIR is indicated for the treatment of adult patients with relapsed or refractory Stage I-III cutaneous T-cell lymphoma (CTCL) after at least one prior systemic therapy.

Important Dosing Instructions Prior to starting each treatment cycle, assess hepatic and renal function. Administer LYMPHIR until disease progression or unacceptable toxicity.

Recommended Premedications

Administer premedications prior to starting a LYMPHIR infusion in Cycles 1 through 3, as outlined in Table 1, to reduce the risk of infusion-related reactions. Table 1. Premedication to be Administered to Patients Prior to LYMPHIR Infusion or higher infusion reaction, premedicate at least 30 minutes prior to each subsequent infusion with a systemic steroid such as dexamethasone 4 mg (or equivalent) via slow intravenous push, for at least 3 cycles.

Dosage Modifications for Adverse Reactions

Dosage modifications for adverse reactions with LYMPHIR are shown in Table 2 below. Table 2: Recommended Interrupt infusion and manage signs and symptoms. Administer steroid premedication prior to the subsequent doses of LYMPHIR Continue steroid premedication for each dose in the next 3 cycles and optional thereafter Based on NCI CTCAE version 5.0 Restarting after Reconstitute and further dilute LYMPHIR prior to administration.

Administer as an intravenous infusion over 60 minutes. Use aseptic technique to prepare LYMPHIR. LYMPHIR does not contain a preservative or anti-microbial agent.

Care should be taken during preparation and administration of LYMPHIR to prevent inadvertent microbial contamination. Reconstitution Calculate the dose (mcg), total volume (mL) of solution required, and number of vials of LYMPHIR needed based on the patient’s actual body weight (kg). More than one vial may be needed for a full dose.

Remove the vial(s) of LYMPHIR from the refrigerator and allow to stand for approximately 30 minutes to reach to room temperature. Reconstitute each LYMPHIR vial with 2.1 mL of Sterile Water for Injection to obtain a final concentration of 150 mcg/mL. If more than one vial is needed to make a complete dose, use a separate syringe and needle for each vial.

Gently swirl the vial. Do not shake. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

The reconstituted solution should be clear and colorless. Discard if the solution is not clear, colorless, and contains particulate matter. Use the reconstituted LYMPHIR solution immediately to prepare the drug product.

Dilution Use only plastic syringes or soft plastic intravenous bags. Do not use glass containers. Maintain concentration of LYMPHIR at 15 mcg/mL or higher during all steps in the preparation of the solution for intravenous infusion.

Withdraw the calculated dose from the vial(s) with a sterile syringe and inject it into an empty intravenous bag. Dilute with 0.9% Sodium Chloride Injection to final concentration of 15 mcg/mL or higher. Do not use if the prepared solution is cloudy or particulates are present.

If not used immediately, store the diluted LYMPHIR solution at room temperature for up to 4 hours. Protect diluted solution from light. Administration Administer infusion solution intravenously over 60 minutes through an intravenous line using a syringe pump or intravenous infusion bag.

Do not administer through in-line filter. Do not mix LYMPHIR with other drugs or administer other drugs through the same infusion line. At the end of the infusion, discard any empty or unused portions of LYMPHIR immediately.

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 the WARNINGS AND PRECAUTIONS reflect exposure to LYMPHIR as a single agent in 119 patients with CTCL across 3 clinical trials. Patients received treatment with LYMPHIR as an intravenous infusion at 9 mcg/kg daily from Day 1 through Day 5 of each 21-day cycle until disease progression or unacceptable toxicity.

Relapsed or Refractory Stage I-III CTCL Study 302 The safety of LYMPHIR was evaluated in Study 302, an open-label, single-arm, multicenter trial that included 69 patients with relapsed or refractory Stage I-III CTCL. Treatment was administered until disease progression or unacceptable toxicity. The median number of LYMPHIR cycles was 6 (range: 1 to 42).

Serious adverse reactions occurred in 38% of patients who received LYMPHIR. Permanent discontinuation of LYMPHIR due to an adverse reaction occurred in 12% of patients. Adverse reactions resulting in permanent discontinuation of LYMPHIR included capillary leak syndrome, infusion-related reaction, renal insufficiency, respiratory failure, and sepsis.

Dosage interruptions of LYMPHIR due to an adverse reaction occurred in 38% of patients. Adverse reactions requiring dosage interruption of LYMPHIR included capillary leak syndrome, infusion-related reaction, weight increase, nausea, and tachycardia. Table 3 summarizes the adverse reactions in Study 302.

Table 3: Adverse Reactions (≥ 10%) in Patients with Relapsed or Refractory Stage I-III CTCL Who Received LYMPHIR in Study 302 0 # Only Grade 3 adverse reaction occurred a Includes fatigue, asthenia, and lethargy b Includes edema, edema peripheral, generalized edema, face edema, swelling face, peripheral swelling c Includes musculoskeletal pain, back pain, neck pain, pain in extremity, myalgia, bone pain d Includes headache, migraine e Includes amnesia, confusional state, delirium, memory impairment, disturbance in attention, somnolence, cognitive disorder f Includes rash, drug eruption, erythema, rash maculo-papular, rash papular, rash pustular, rash pruritic, dermatitis exfoliative generalized, acute generalized exanthematous pustulosis g Includes skin infection, skin bacterial infection, staphylococcal skin infection, impetigo h Includes acute kidney injury, blood creatinine increased Clinically relevant adverse reactions in < 10% of patients who received LYMPHIR included sepsis and peripheral neuropathy. Table 4 summarizes select laboratory abnormalities in Study 302. Table 4: Select Laboratory Abnormalities (≥ 10%) that Worsened from Baseline in Patients with Relapsed or Refractory Stage I-III CTCL who Received LYMPHIR in Study 302 a Graded according to NCI CTCAE version 5.0 b The denominator used to calculate the rate was 67 based on the number of patients with a baseline value and at least one post-treatment value c Percentage of patients with an increase of at least 1 CTCAE grade from baseline to the worst post-baseline value of any grade, or to the worst post-baseline value that is Grade 3 or 4 d The denominator used to calculate the rate was based on 36 patients with a baseline value and at least one post-treatment value. 6. 2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of denileukin diftitox.

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. Thyroid conditions: hyperthyroidism, thyroiditis, thyrotoxicosis, and hypothyroidism.

Pregnancy Risk Summary Based on its mechanism of action, LYMPHIR can cause fetal harm when administered to a pregnant woman. There are no available data on the use of LYMPHIR in pregnant women to evaluate for a drug-associated risk. No animal reproductive and developmental toxicity studies have been conducted with denileukin diftitox.

Denileukin diftitox-cxdl causes depletion of regulatory T lymphocytes (Treg), immune activation, and capillary leak syndrome, compromising pregnancy maintenance. 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 are 2-4% and 15-20%, respectively.

Pediatric Use Safety and effectiveness of LYMPHIR in pediatric patients have not been established.