Imlygic Drug Information

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.

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 . 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 . 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 . 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 6 46 1 (< 1) Chills 142 11 Pyrexia 125 11 Influenza-like illness 89 2 (< 1) 19 Injection site pain 81 2 (< 1) 8 Gastrointestinal disorders Nausea 104 1 (< 1) 25 Vomiting 62 5 12 Diarrhea 55 1 (< 1) 14 Constipation 34 8 1 (< 1) Abdominal pain 26 2 (< 1) 3 Musculoskeletal and connective tissue disorders Myalgia 51 1 (< 1) 7 Arthralgia 50 2 (< 1) 11 Pain in extremity 48 4 12 1 (< 1) Nervous system disorders Headache 55 2 (< 1) 12 Dizziness 28 4 Respiratory, thoracic, and mediastinal disorders Oropharyngeal pain 17 1 (< 1) Investigations Weight decreased 17 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.

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. Serious including fatal disseminated herpetic infections in immunocompromised patient population.

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 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.

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.

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

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 .

Pregnant Patients Do not administer

IMLYGIC to pregnant patients.

There is no clinical experience with an overdose with IMLYGIC. Doses up to 4 mL at dose strength of 10 8 (100 million) PFU per mL every 2 weeks (maximum cumulative dose of 222.5 x 10 8 PFU) have been administered in clinical studies, with no evidence of dose-limiting toxicity. The maximum dose of IMLYGIC that can be safely administered has not been determined. In the event of a suspected overdose, the patient should be treated symptomatically and supportive measures instituted as required .