IMLYGIC

IMLYGIC (talimogene laherparepvec) is a sterile suspension for intralesional injection. IMLYGIC is a live, attenuated HSV-1 that has been genetically modified to express huGM-CSF. The parental virus for IMLYGIC was a primary isolate, which was subsequently altered using recombinant methods to result in gene deletions and insertions. Each vial contains 1 mL deliverable volume of IMLYGIC at either 1 x 10 6 (1 million) PFU per mL or 1 × 10 8 (100 million) PFU per mL concentrations and the following excipients: di-sodium hydrogen phosphate dihydrate (15.4 mg), sodium dihydrogen phosphate dihydrate (2.44 mg), sodium chloride (8.5 mg), myo-inositol (40 mg), sorbitol (20 mg), and water for injection. The 10 6 (1 million) PFU per mL vial of IMLYGIC contains a clear to semi-translucent liquid following thaw from its frozen state. The 10 8 (100 million) PFU per mL vial of IMLYGIC contains a semi-translucent to opaque liquid following thaw from its frozen state. The liquid in each vial may contain white, visible, variously shaped, virus-containing particles. Each vial of IMLYGIC may also contain residual components of VERO cells including DNA and protein and trace quantities of fetal bovine serum. The product contains no preservative.

IMLYGIC is a genetically modified oncolytic viral therapy indicated for the local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrent after initial surgery. Limitations of use : IMLYGIC has not been shown to improve overall survival or have an effect on visceral metastases. IMLYGIC is a genetically modified oncolytic viral therapy indicated for the local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrent after initial surgery. Limitations of use : IMLYGIC has not been shown to improve overall survival or have an effect on visceral metastases. ( 1 )

For intralesional injection only. Do not administer intravenously. Administer IMLYGIC by injection into cutaneous, subcutaneous, and/or nodal lesions. ( 2.1 ) Recommended starting dose is up to a maximum of 4 mL of IMLYGIC at a concentration of 10 6 (1 million) plaque-forming units (PFU) per mL. Subsequent doses should be administered up to 4 mL of IMLYGIC at a concentration of 10 8 (100 million) PFU per mL. ( 2.1 ) 2.1 Dose Administer IMLYGIC by injection into cutaneous, subcutaneous, and/or nodal lesions that are visible, palpable, or detectable by ultrasound guidance. IMLYGIC is provided in single-dose vials of 1 mL each in two different dose strengths: 10 6 (1 million) plaque-forming units (PFU) per mL (light green cap) – for initial dose only 10 8 (100 million) PFU per mL (royal blue cap) – for all subsequent doses Recommended Dose and Schedule The total injection volume for each treatment visit should not exceed 4 mL for all injected lesions combined. It may not be possible to inject all lesions at each treatment visit or over the full course of treatment. Previously injected and/or uninjected lesion(s) may be injected at subsequent treatment visits. The initial recommended dose is up to 4 mL of IMLYGIC at a concentration of 10 6 (1 million) PFU per mL. The recommended dose for subsequent administrations is up to 4 mL of IMLYGIC at a concentration of 10 8 (100 million) PFU per mL. The recommended dosing schedule for IMLYGIC is shown in Table 1. Table 1. Recommended Dose and Schedule for IMLYGIC Treatment Treatment I nterval Maximum I njection V olume per T reatme n t V isit (all lesions combined) Dose S trength Prioritization of L esions to be I njected Initial – 4 mL 10 6 (1 million) PFU per mL Inject largest lesion(s) first. Prioritize injection of remaining lesion(s) based on lesion size until maximum injection volume is reached or until all injectable lesion(s) have been treated. Second 3 weeks after initial treatment 4 mL 10 8 (100 million) PFU per mL Inject any new lesion(s) (lesions that have developed since initial treatment) first. Prioritize injection of remaining lesion(s) based on lesion size until maximum injection volume is reached or until all injectable lesion(s) have been treated. All subsequent treatments (including reinitiation) 2 weeks after previous treatment 4 mL 10 8 (100 million) PFU per mL Inject any new lesion(s) (lesions that have developed since previous treatment) first. Prioritize injection of remaining lesion(s) based on lesion size until maximum injection volume is reached or until all injectable lesion(s) have been treated. Dose Volume Determination (per Lesion) Use Table 2 to determine the volume of IMLYGIC injection for each lesion. Table 2. Determination of IMLYGIC Injection Volume Based on Lesion Size Lesion Size (longest dimension) Injection Volume > 5 cm up to 4 mL > 2.5 cm to 5 cm up to 2 mL > 1.5 cm to 2.5 cm up to 1 mL > 0.5 cm to 1.5 cm up to 0.5 mL ≤ 0.5 cm up to 0.1 mL When lesions are clustered together, inject them as a single lesion according to Table 2. Continue IMLYGIC treatment for at least 6 months unless other treatment is required or until there are no injectable lesions to treat. Reinitiate IMLYGIC treatment if new unresectable cutaneous, subcutaneous, or nodal lesions appear after a complete response. 2.2 Preparation and Handling Healthcare providers who are immunocompromised or pregnant should not prepare or administer IMLYGIC and should not come into direct contact with the IMLYGIC injection sites, dressings, or body fluids of treated patients [see Warnings and Precautions ( 5.1 )] . Avoid accidental exposure to IMLYGIC and follow below instructions for preparation, administration, and handling of IMLYGIC: Wear personal protective equipment (protective gown or laboratory coat, safety glasses or face shield, and gloves) while preparing or administering IMLYGIC. Avoid accidental exposure to IMLYGIC, especially contact with skin, eyes, and mucous membranes. ○ Cover any exposed wounds before handling. ○ In the event of an accidental occupational exposure (e.g., through a splash to the eyes or mucous membranes), flush with clean water for at least 15 minutes. ○ In the event of exposure to broken skin or needle stick, clean the affected area thoroughly with soap and water and/or a disinfectant. Clean all surfaces that may have come in contact with IMLYGIC and treat all IMLYGIC spills with a virucidal agent such as 1% sodium hypochlorite or 70% isopropyl alcohol and blot using absorbent materials. Dispose of all materials that may have come in contact with IMLYGIC (e.g., vial, syringe, needle, cotton gauze, gloves, masks, or dressings) as biohazardous waste. Advise patients to place used dressings and cleaning materials into a sealed plastic bag and dispose in household waste. Thawing IMLYGIC Vials 1. Determine the total volume required for injection, up to 4 mL [see Dosage and Administration (2.1) ]. 2. Thaw frozen IMLYGIC vials at room temperature [20°C to 25°C (68°F to 77°F)] until IMLYGIC is liquid. The time to achieve complete vial thaw is expected to be 30 to 70 minutes, depending on the ambient temperature. Do not expose the vial to higher temperatures. Keep the vial in original carton during thawing. 3. Swirl gently. Do NOT shake. 4. After thawing, administer IMLYGIC immediately or store in its original vial and carton, as follows: Thawed IMLYGIC is stable when stored at temperatures of 2°C (36°F) up to 25°C (77°F) protected from light in its original vial and carton for the storage times specified in Table 3. Do not exceed the storage times specified in Table 3. IMLYGIC must not be refrozen once it is thawed. Discard any thawed IMLYGIC in the vial stored longer than the specified times in Table 3. Table 3. Maximum Storage Time for Thawed Imlygic in Vial 10 6 (1 million) PFU / mL 10 8 (100 million) PFU / mL 2°C to 8°C (36°F to 46°F) 24 hours 1 week (7 days) up to 25°C (77°F) 12 hours 24 hours 5. Prepare sterile syringes and needles. A detachable 18-26 G needle or nondetachable 22-26 G staked needle (which minimizes hold up volume) may be used for IMLYGIC withdrawal and a detachable or nondetachable staked needle of 22–26 G may be used for injection. Small unit syringes (e.g., 0.5 mL insulin syringes) are recommended for better injection control. 6. Using aseptic technique, remove the vial cap and withdraw the product from the vial into the syringe(s), noting the total volume. Avoid generating aerosols when loading syringes with product and use a biologic safety cabinet if available. 2.3 Administration Follow the steps below to administer IMLYGIC to patients: Pre-Injection Clean the lesion and surrounding areas with an alcohol swab and let dry. Treat the injection site with a topical or local anesthetic agent, if necessary. Do not inject anesthetic agent directly into the lesion. Inject anesthetic agent around the periphery of the lesion. Injection Inject IMLYGIC intralesionally into cutaneous, subcutaneous, and/or nodal lesions that are visible, palpable, or detectable by ultrasound guidance. Using a single insertion point, inject IMLYGIC along multiple tracks as far as the radial reach of the needle allows within the lesion to achieve even and complete dispersion. Multiple insertion points may be used if a lesion is larger than the radial reach of the needle. Figure 1: Injection administration for cutaneous lesions Figure 2: Injection administration for subcutaneous lesions Figure 3: Injection administration for nodal lesions Inject IMLYGIC evenly and completely within the lesion by pulling the needle back without exiting the lesion. Redirect the needle as many times as necessary while injecting the remainder of the dose of IMLYGIC. Continue until the full dose is evenly and completely dispersed. When removing the needle, withdraw it from the lesion slowly to avoid leakage of IMLYGIC at the insertion point. Repeat steps 1-2 under pre-injection and steps 1-3 under injection for other lesions to be injected. Use a new needle any time the needle is completely removed from a lesion and each time a different lesion is injected. Figure 1 Figure 2 Figure 3 Post-Injection Apply pressure to the injection site(s) with sterile gauze for at least 30 seconds. Swab the injection site(s) and surrounding area with alcohol. Change gloves and cover the injected lesion(s) with an absorbent pad and dry occlusive dressing. Wipe the exterior of occlusive dressing with alcohol. Advise patients to: Keep the injection site(s) covered for at least the first week after each treatment visit or longer if the injection site is weeping or oozing. Replace the dressing if it falls off.

Immunocompromised Patients ( 4.1 ) Pregnant Patients ( 4.2 ) 4.1 Immunocompromised Patients IMLYGIC is a live, attenuated herpes simplex virus and may cause life-threatening disseminated herpetic infection in patients who are immunocompromised. Do not administer IMLYGIC to immunocompromised patients, including those with a history of primary or acquired immunodeficient states, leukemia, lymphoma, AIDS or other clinical manifestations of infection with human immunodeficiency viruses, and those on immunosuppressive therapy [see Nonclinical Toxicology ( 13.2 )] . 4.2 Pregnant Patients Do not administer IMLYGIC to pregnant patients.

The most commonly reported adverse drug reactions (≥ 25%) in IMLYGIC-treated patients were fatigue, chills, pyrexia, nausea, influenza-like illness, and injection site pain. The following adverse reactions are discussed in greater detail in another section of the label: Herpetic Infection [see Warnings and Precautions ( 5.2 )] Injection Site Complications [see Warnings and Precautions ( 5.3 )] The most commonly reported adverse drug reactions (≥ 25%) in IMLYGIC-treated patients were fatigue, chills, pyrexia, nausea, influenza-like illness, and injection site pain. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Amgen at 1-855-IMLYGIC (1-855-465-9442) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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 safety of IMLYGIC was evaluated in 419 patients who received at least 1 dose of either IMLYGIC (n = 292) or subcutaneously administered granulocyte-macrophage colony-stimulating factor (GM-CSF) (n = 127) in an open-label, randomized clinical study of patients with stage IIIB, IIIC, and IV melanoma that was not considered to be surgically resectable [see Clinical Studies ( 14 )] . The median duration of exposure to IMLYGIC was 23 weeks (5.3 months). Twenty-six patients were exposed to IMLYGIC for at least 1 year. Most adverse reactions reported were mild or moderate in severity and generally resolved within 72 hours. The most common grade 3 or higher adverse reaction was cellulitis [see Warnings and Precautions ( 5.3 )] . Pyrexia, chills, and influenza-like illness can occur any time during IMLYGIC treatment but were more frequent during the first 3 months of treatment. Table 4 below lists adverse reactions with a 5% or greater incidence in the IMLYGIC arm compared to the GM-CSF arm in the clinical study [see Clinical Studies ( 14 )] . Table 4. Adverse Reactions Reported with At Least a 5% Greater Incidence in Patients Treated with IMLYGIC Compared to GM-CSF Adverse Reactions IMLYGIC ( n = 292) GM-CSF ( n = 127) Any Grade n (%) Grade 3 n (%) Any Grade n (%) Grade 3 n (%) General disorders and administration site conditions Fatigue 147 (50.3) 6 (2.1) 46 (36.2) 1 (< 1) Chills 142 (48.6) 11 (8.7) Pyrexia 125 (42.8) 11 (8.7) Influenza-like illness 89 (30.5) 2 (< 1) 19 (15.0) Injection site pain 81 (27.7) 2 (< 1) 8 (6.3) Gastrointestinal disorders Nausea 104 (35.6) 1 (< 1) 25 (19.7) Vomiting 62 (21.2) 5 (1.7) 12 (9.5) Diarrhea 55 (18.8) 1 (< 1) 14 (11.0) Constipation 34 (11.6) 8 (6.3) 1 (< 1) Abdominal pain 26 (8.9) 2 (< 1) 3 (2.4) Musculoskeletal and connective tissue disorders Myalgia 51 (17.5) 1 (< 1) 7 (5.5) Arthralgia 50 (17.1) 2 (< 1) 11 (8.7) Pain in extremity 48 (16.4) 4 (1.4) 12 (9.5) 1 (< 1) Nervous system disorders Headache 55 (18.8) 2 (< 1) 12 (9.5) Dizziness 28 (9.6) 4 (3.2) Respiratory, thoracic , and mediastinal disorders Oropharyngeal pain 17 (5.8) 1 (< 1) Investigations Weight decreased 17 (5.8) 1 (< 1) 1 (< 1) Other adverse reactions associated with IMLYGIC in the open-label, randomized study include rash, dermatitis, glomerulonephritis, vitiligo, worsening psoriasis, cellulitis, pneumonitis, vasculitis, herpetic keratitis, obstructive airway disorder, plasmacytoma at the injection site, deep vein thrombosis, and oral herpes. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of IMLYGIC. 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. Herpetic infections including disseminated herpetic infections [see Warnings and Precautions (5.2) ]. Serious including fatal disseminated herpetic infections in immunocompromised patient population [see Contraindications (4.1) and Warnings and Precautions (5.2) ].

IMLYGIC is sensitive to acyclovir. Acyclovir or other antiherpetic viral agents may interfere with the effectiveness of IMLYGIC. No drug interaction studies have been conducted with IMLYGIC.