Imlygic

         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:

• 106 (1 million) plaque-forming units (PFU) per mL (light green cap) – for initial dose only
  
• 108 (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 106 (1 million) PFU per mL. The recommended dose for subsequent administrations is up to 4 mL of IMLYGIC at a concentration of 108 (100 million) PFU per mL. The recommended dosing schedule for IMLYGIC is shown in Table 1.

Dose Volume Determination (per Lesion)

Use Table 2 to determine the volume of IMLYGIC injection for each lesion.

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.

         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.

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.

         Administration

Follow the steps below to administer IMLYGIC to patients:

         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 108 (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.

         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.

         Females and Males of Reproductive Potential

No nonclinical or clinical studies were performed to evaluate the effect of IMLYGIC on fertility.

         Pediatric Use

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

         Geriatric Use

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

         Renal Impairment

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

         Hepatic Impairment

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

         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.

         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.

         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.

         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.

         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.

         Obstructive Airway Disorder

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

         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.