Imlygic

1 INDICATIONS AND USAGE 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 )

2 DOSAGE AND ADMINISTRATION 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…

5 WARNINGS AND PRECAUTIONS Accidental Exposure to IMLYGIC: Accidental exposure may lead to transmission of IMLYGIC and herpetic infection. Healthcare providers and close contacts should avoid direct contact with injected lesions, dressings, or body fluids of treated patients. Accidental Exposure to IMLYGIC continued: Healthcare providers who are immunocompromised or pregnant should not prepare or administer IMLYGIC. If accidental exposure occurs, exposed individuals should clean the affected area. ( 5.1 ) Herpetic Infection: Patients who develop herpetic infections should be advised to follow standard hygienic practices to prevent viral transmission. ( 5.2 ) Injection Site Complications: Consider the risks and benefits before continuing IMLYGIC treatment if persistent infection or delayed healing develops. ( 5.3 ) Immune-Mediated Events: Consider the risks and benefits of IMLYGIC before initiating treatment in patients who have underlying autoimmune disease or before continuing treatment in patients who develop immune-mediated events. ( 5.4 ) Plasmacytoma at the Injection Site: Consider the risks and benefits in patients with multiple myeloma or in whom plasmacytoma develops during treatment. ( 5.5 ) Obstructive Airway Disorder: Use caution when injecting lesions close to major airways. ( 5.6 ) Hepatic Hemorrhage from Transcutaneous Intrahepatic Route of Administration: IMLYGIC is not indicated for treatment via transcutaneous intrahepatic route of administration. ( 5.7 ) 5.1 Accidental Exposure to IMLYGIC Accidental exposure may lead to transmission of IMLYGIC and herpetic infection. Accidental needle stick and splashback to the eyes have been reported in healthcare providers during preparation and administration of IMLYGIC. Healthcare providers, close contacts (household members, caregivers, sex partners, or persons sharing the same bed), pregnant women, and newborns should avoid direct contact with injected lesions, dressings, or body fluids of treated patients [ see Dosage and Administration ( 2.2 )] . Healthcare providers who are immunocompromised or pregnant should not prepare or administer IMLYGIC. Caregivers should wear protective gloves when assisting patients in applying or changing occlusive dressings and observe safety precautions for disposal of used dressings, gloves, and cleaning materials [ see Dosage and Administration ( 2.2 ) ] . In the event of an accidental exposure to IMLYGIC, exposed individuals should clean the affected area thoroughly with soap and water and/or a disinfectant. If signs or symptoms of herpetic infection develop, the exposed individuals should contact their healthcare provider for appropriate treatment [ see Warnings and Precautions ( 5.2 )] . Patients should avoid touching or scratching injection sites or their occlusive dressings, as doing so could lead to inadvertent transfer of IMLYGIC to other areas of the body. 5.2 Herpetic Infection Herpetic infections (including but not limited to cold sores and herpetic keratitis) and serious cases of disseminated herpetic infections have been reported in patients treated with IMLYGIC, including fatal disseminated herpetic infection in the immunocompromised patient population [see Clinical Trials Experience (6.1) and Postmarketing Experience (6.2) ] . Immunocompromised patients may be at increased risk of life-threatening disseminated herpetic infection [see Contraindications (4.1) ] . Patients who develop suspicious herpes-like lesions should follow standard hygienic practices to prevent viral transmission. Patients or close contacts with suspected herpetic infections should also contact their healthcare provider to evaluate the lesions. Suspected herpetic lesions should be reported to Amgen at 1-855-IMLYGIC (1-855-465-9442); patients or close contacts have the option of follow-up testing for further characterization of the infection. IMLYGIC is sensitive to acyclovir. Acyclovir or other antiviral agents may interfere with the effectiveness of I…

4 CONTRAINDICATIONS 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.

7 DRUG INTERACTIONS 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.

8.1 Pregnancy Risk Summary Adequate and well-controlled studies with IMLYGIC have not been conducted in pregnant women. No effects on embryo-fetal development have been observed in a study conducted in pregnant mice. The design of the study limits application of the animal data to humans [see Data]. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations If the patient becomes pregnant while taking IMLYGIC, the patient should be apprised of the potential hazards to the fetus and neonate. Women of childbearing potential should be advised to use an effective method of contraception to prevent pregnancy during treatment with IMLYGIC. If a pregnant woman has an infection with wild-type Herpes Simplex Virus Type 1 (HSV-1) (primary or reactivation), there is potential for the virus to cross the placental barrier and also a risk of transmission during birth due to viral shedding. Infections with wild-type HSV-1 have been associated with serious adverse effects, including multi-organ failure and death, if a fetus or neonate contracts the wild-type herpes infection. While there are no clinical data to date on IMLYGIC infections in pregnant women, there could be a risk to the fetus or neonate if IMLYGIC were to act in the same manner. Data Animal Data No effects on embryo-fetal development were observed when IMLYGIC was intravenously administered during organogenesis to immunocompetent pregnant mice at doses up to 4 x 10 8 (400 million) PFU per kg (60-fold higher, on a PFU per kg basis, compared to the maximum clinical dose). Levels of IMLYGIC DNA in pooled fetal blood were at or below the assay detection level. Study design limitations included: 1) administration of IMLYGIC expressing human granulocyte-macrophage colony-stimulating factor (huGM-CSF), which is not biologically active in mice; 2) unknown transplacental kinetics of IMLYGIC following intravenous administration in pregnant mice; and 3) unknown significance of IMLYGIC dose extrapolation from animal to human based on body weight.

6 ADVERSE REACTIONS 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 imm…