Talimogene Laherparepvec

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 )

Initial dose only: 10 6 (1 million) PFU per mL solution in 1 mL single-dose vial (light green cap) Subsequent doses: 10 8 (100 million) PFU per mL solution in 1 mL single-dose vial (royal blue cap) Injection: 10 6 (1 million) PFU per mL, 10 8 (100 million) PFU per mL in single-dose vials ( 3 )

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.

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 IMLYGIC. Therefore, consider the risks and benefits of IMLYGIC treatment before administering antiviral agents to manage herpetic infection.

5.3 Injection Site Complications Necrosis or ulceration of tumor tissue may occur during IMLYGIC treatment. Cellulitis and systemic bacterial infection have been reported in clinical studies. Careful wound care and infection precautions are recommended, particularly if tissue necrosis results in open wounds. In clinical studies, impaired healing at the injection site has been reported. IMLYGIC may increase the risk of impaired healing in patients with underlying risk factors (e.g., previous radiation at the injection site or lesions in poorly vascularized areas). One patient had an amputation of a lower extremity 6 months after IMLYGIC injection due to an infected non-healing wound. This wound area had been treated with surgery and radiation prior to IMLYGIC treatment and had previous wound complications. If there is persistent infection or delayed healing of the injection site(s), consider the risks and benefits of IMLYGIC before continuing treatment with IMLYGIC.

5.4 Immune-Mediated Events IMLYGIC may result in immune-mediated events. In clinical studies, immune-mediated events, including glomerulonephritis, vasculitis, pneumonitis, worsening psoriasis, and vitiligo have been reported in patients treated with IMLYGIC. 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.

5.5 Plasmacytoma at the Injection Site In a clinical study, a plasmacytoma has been reported in proximity to the injection site after administration of IMLYGIC in a patient with smoldering multiple myeloma. Consider the risks and benefits of IMLYGIC in patients with multiple myeloma or in whom plasmacytoma develops during treatment.

5.6 Obstructive Airway Disorder Obstructive airway disorder has been reported following IMLYGIC treatment. Use caution when injecting lesions close to major airways.

5.7 Hepatic Hemorrhage from Transcutaneous Intrahepatic Route of Administration IMLYGIC is not indicated for transcutaneous intrahepatic route of administration. In clinical studies, cases of hepatic hemorrhage resulting in hospitalization and death have been reported in patients receiving transcutaneous intrahepatic IMLYGIC injections.

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.

Pregnancy: Women of childbearing potential should be advised to use an effective method of contraception to prevent pregnancy during treatment with IMLYGIC. ( 8.1 ) Lactation: Discontinue drug or nursing. ( 8.2 )

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.

8.2 Lactation Risk Summary There is no information regarding the presence of IMLYGIC in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for IMLYGIC and any potential adverse effects on the breastfed infant from IMLYGIC or from the underlying maternal condition. Clinical Considerations Because medicinal products can be found in human milk, a decision should be made whether to discontinue nursing or to discontinue IMLYGIC while nursing.

8.3 Females and Males of Reproductive Potential No nonclinical or clinical studies were performed to evaluate the effect of IMLYGIC on fertility.

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

8.5 Geriatric Use In clinical studies, no overall differences in safety or efficacy were observed between geriatric patients (≥ 65 years old) and younger patients.

8.6 Renal Impairment No clinical studies have been conducted to evaluate the effect of renal impairment on the pharmacokinetics of IMLYGIC.

8.7 Hepatic Impairment No clinical studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of IMLYGIC.

IMLYGIC has been genetically modified to replicate within tumors and to produce the immune stimulatory protein GM-CSF. IMLYGIC causes lysis of tumors, followed by release of tumor-derived antigens, which together with virally derived GM-CSF may promote an antitumor immune response. However, the exact mechanism of action is unknown.