Consumer medicine information

Imlygic Solution for injection

Talimogene laherparepvec

BRAND INFORMATION

Brand name

Imlygic Solution for injection

Active ingredient

Talimogene laherparepvec

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Imlygic Solution for injection.

What is in this leaflet

This leaflet answers some common questions about Imlygic. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you using Imlygic against the benefits they expect it will have for you.

If you have any concerns about using this medicine, ask your doctor, nurse or pharmacist.

Keep this leaflet.

You may need to read it again.

What Imlygic is used for

Imlygic is used to treat a type of skin cancer called melanoma that has spread in the skin and/or to the lymph nodes.

Imlygic contains a weakened form of herpes simplex virus type-1 (HSV-1), which is commonly called the cold sore virus. The virus has been altered to be able to make GM-CSF (Granulocyte-Macrophage Colony-Stimulating Factor), a protein which helps your body's immune system recognise and destroy tumours. When Imlygic is injected into tumours it destroys the melanoma.

Imlygic also helps your immune system to destroy melanoma throughout your body.

Ask your doctor if you have any questions about why this medicine has been prescribed for you.

Your doctor may have prescribed it for another reason.

This medicine is available only with a doctor's prescription.

Before you are given Imlygic

When you must not be given it

Do not have Imlygic if you have an allergy to:

  • any medicine containing talimogene laherparepvec
  • any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

  • shortness of breath, wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin .

Do not have this medicine if you have a:

  • severely lowered immunity

Do not have Imlygic after the expiry date printed on the pack.

Do not have Imlygic if the packaging is torn or shows signs of tampering.

If you are not sure whether you should have Imlygic, talk to your doctor.

Before you are given it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have or have had any of the following medical conditions:

  • lowered immunity due to diseases including HIV/AIDS, blood or bone marrow cancer
  • lowered immunity due to treatment with medicines such as steroids or other medicines that lower your immune system
  • autoimmune disease (a condition where the body attacks itself)
  • multiple myeloma (cancer of blood cells).
  • if you have never had herpes infections before

Tell your doctor if you are pregnant or plan to become pregnant.

Imlygic may affect your developing baby. If it is necessary for you to have Imlygic your doctor will discuss the risks and benefits of having it during pregnancy.

Females who are able to become pregnant should use suitable birth control (contraception) methods during treatment with Imlygic.

Talk to your doctor about birth control methods (contraception) that may be right for you.

Tell your doctor if you are breast-feeding or plan to breast feed.

It is not known if Imlygic passes into breast milk. You and your doctor should decide if you should take Imlygic or breast feed. You should not do both.

If you have not told your doctor about any of the above, tell him/her before you use Imlygic.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

Tell your doctor if you are taking:

  • anti-viral medicines to treat or prevent herpes, such as Famvir, Valtrex or Zovirax

These medicines may be affected by Imlygic, or may affect how well it works. You may need to use different amounts of your medicines, or take different medicines.

Your doctor or pharmacist has more information on medicines to be careful with or avoid while taking Imlygic.

How Imlygic is given

Imlygic is given as an injection into your tumour cells.

Your doctor will decide which tumours to inject and may not inject every tumour.

Your existing tumour(s) may increase in size and new tumour(s) could appear while you are being treated with Imlygic.

Your second injection of Imlygic is given 3 weeks after the first injection. Then Imlygic injections are every 2 weeks for as long as you have tumour(s).

Follow all directions given to you by your doctor, nurse or pharmacist carefully.

They may differ from the information contained in this leaflet.

If you do not understand the instructions, ask your doctor or pharmacist for help.

How long to use it

You can expect to be treated with this medicine for 6 months or longer.

If you miss a dose

If you miss a dose, talk to your doctor and arrange another visit as soon as possible.

While you are using Imlygic

Things you must do

Tell any other doctors, nurses dentists, and pharmacists who treat you that you are taking this medicine.

If you become pregnant while taking this medicine, tell your doctor immediately.

Keep all of your doctor's appointments so that your progress can be checked.

Avoid direct contact of injection sites or body fluids (blood, urine, saliva) with close contacts.

Close contacts include household members, caregivers, sex partners, or someone you share a bed with:

  • use latex condoms when engaging in sexual activity
  • avoid kissing close contacts if either of you has an open mouth sore while you are being treated and until 30 days after your last dose.

Your close contacts could be accidently exposed to Imlygic, if they have direct contact with your body fluids or injection sites.

Tell your doctor if you have any close contact who has a lowered immune system or is pregnant.

Your doctor may have special instructions for them.

Care for your injection sites properly:

  • avoid touching or scratching the injection sites
  • keep injection sites covered at all times with watertight dressings. If the dressing comes loose or falls off, replace it with a clean dressing
  • place all used dressings and cleaning materials in a sealed plastic bag and throw them away in your household waste.
  • keep used dressings and cleaning materials away from infants less than 3 months old.

Tell your close contacts to:

  • avoid direct contact with your body fluids or injection sites
  • cover any exposed wounds and wear gloves while changing your dressing
  • clean any area with soap and water and/or a disinfectant if accidentally exposed to Imlygic, body fluids or injections sites
  • contact their doctor immediately if they develop symptoms of herpes infection:
    - pain, burning or tingling, in a blister around the mouth or genitals, or on the fingers or ears
    - eye pain, light sensitivity, discharge from the eyes, redness of eye, watery or blurry vision
    - flu-like illness (fever, chills, tiredness or headache)
    - weakness in arms or legs
  • other rare symptoms include mental confusion, memory loss and seizures.

Close contacts that have a lowered immune system or are pregnant should not touch injection sites, used dressings and cleaning materials, or change your dressings or clean your injection sites.

Things to be careful of

If you have cold sores or other signs of herpes infection, use good hygiene habits and contact your doctor immediately.

Some of the symptoms of cold sores or herpes infection may include:

  • pain, burning or tingling, in a blister around the mouth or genitals, or on the fingers or ears
  • eye pain, light sensitivity, discharge from the eyes, redness of eye, watery or blurry vision
  • flu-like illness (fever, chills, tiredness or headache)
  • weakness in arms or legs
  • other rare symptoms include mental confusion, memory loss and seizures.

Tell your doctor or nurse as soon as possible if your injection site is not healing.

Avoid direct contact of infants less than 3 months old to body fluids (eg blood, urine, saliva) of the treated patient, injection site or contaminated materials. If your infant shows signs of herpes infection, contact your doctor immediately.

Side effects

Tell your doctor, nurse or pharmacist as soon as possible if you do not feel well after being given Imlygic.

This medicine helps most people with melanoma, but it may have unwanted side effects in a few people.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor or pharmacist if you notice any of the following and they worry you:

  • pain in general, after procedure, or in underarm, abdomen, limbs, groin, back, throat, tumour, ear
  • tiredness or generally feeling unwell
  • flu like illness, fever or chills, cough
  • feeling sick or vomiting, stomach discomfort or diarrhoea
  • constipation
  • muscle pain or painful/swollen joints, bruising
  • redness in the face
  • dizziness
  • headache
  • areas of skin without any colour
  • rash, inflamed skin, or worsening skin scaling
  • feeling confused, anxious or feeling depressed
  • difficulty falling asleep
  • swelling of hands, ankles or feet without pain

The above list includes the more common side effects of your medicine. They are usually mild and short-lived.

Tell your doctor as soon as possible if you notice any of the following:

  • dehydration
  • weight loss
  • fast heart rate

Tell your doctor immediately if any of the following happen:

  • cold sores or other signs of herpes infection
  • redness, swelling, discharge, or warmth at the injection site.

Tell your doctor immediately, or go to Accident and Emergency at your nearest hospital, if you notice any of the following:

  • pain with swelling and tenderness in one of the legs
  • shortness of breath or difficulty breathing

The above list includes serious side effects that may require medical attention or hospitalisation.

Tell your doctor if you notice anything that is making you feel unwell.

Other side effects not listed above may occur in some people. Tell your doctor if you notice anything that is making you feel unwell.

Do not be alarmed by this list of possible side effects.

You may not experience any of them.

Storing Imlygic

Imlygic is stored at the doctor's surgery or clinic, or at the pharmacy.

Disposal

Your doctor, nurse or pharmacist will dispose of this medicine.

Product description

What it looks like

Imlygic when thawed is a clear to semi-translucent or opaque liquid.

It is supplied in a single use vial, containing either:

  • 1 million plaque forming units (PFU) in a volume of 1.0 mL or
  • 100 million PFU in a volume of 1.0 mL.

Ingredients

Active ingredient: talimogene laherparepvec.

The other ingredients are:

  • sodium phosphate - dibasic dihydrate
  • sodium phosphate - monobasic dihydrate
  • sodium chloride
  • inositol
  • sorbitol
  • water for injections.

This medicine does not contain lactose, sucrose, gluten, tartrazine or any other azo dyes.

Manufacturer/Supplier

This medicine is made in the USA and supplied in Australia by:

Amgen Australia Pty Ltd
ABN 31 051 057 428
Level 7 123 Epping Road
North Ryde, NSW, 2113

This leaflet was prepared in December 2015.

Imlygic 1 million PFU AUST R 232296
Imlygic 100 million PFU AUST R 232297

BRAND INFORMATION

Brand name

Imlygic Solution for injection

Active ingredient

Talimogene laherparepvec

Schedule

S4

 

1 Name of Medicine

Talimogene laherparepvec (rmv).

6.7 Physicochemical Properties

Chemical structure.

Talimogene laherparepvec is an attenuated herpes simplex virus type-1 (HSV-1) derived by functional deletion of 2 genes (ICP34.5 and ICP47) and insertion of coding sequence for human granulocyte macrophage colony-stimulating factor (GM-CSF) (see Section 2 Qualitative and Quantitative Composition).

CAS number.

1187560-31-1.

2 Qualitative and Quantitative Composition

Talimogene laherparepvec is attenuated herpes simplex virus type-1 (HSV-1) derived by functional deletion of 2 genes (ICP34.5 and ICP47) and insertion of coding sequence for human granulocyte macrophage colony-stimulating factor (GM-CSF) (see Section 5.1 Pharmacodynamic Properties, Mechanism of action).
Talimogene laherparepvec is produced in vero cells by recombinant DNA technology.
Each single-use vial contains 1 mL deliverable volume of Imlygic at a nominal concentration of 1 x 106 (1 million) PFU/mL or 1 x 108 (100 million) PFU/mL Imlygic.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Imlygic is a sterile, preservative free solution for intralesional injection.
Following thaw the liquid is clear to semi-translucent (106 plaque forming units (PFU)/mL) or semi-translucent to opaque (108 PFU/mL) and may contain white, visible, variously shaped, virus-containing particles.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Imlygic is an oncolytic immunotherapy that is derived from HSV-1. Imlygic has been modified to replicate within tumours and to produce the immune stimulatory protein GM-CSF. Imlygic causes lytic tumour cell death and release of tumour derived antigens and GM-CSF, which together promote a systemic antitumour immune response.
The modifications to derive Imlygic from HSV-1 include deletion of ICP34.5 and ICP47. Whereas antiviral immune responses defend normal tissues following infection by Imlygic, tumours have been shown to be susceptible to injury and cell death from ICP34.5 deficient HSV-1 viruses, including Imlygic. GM-CSF recruits and activates antigen presenting cells which can process and present tumour derived antigens to promote an effector T cell response.

Clinical trials.

Metastatic melanoma.

Study 1.

The safety and efficacy of Imlygic compared with subcutaneously administered GM-CSF was evaluated in a phase 3, multicentre, open label and randomised clinical study of patients with stage IIIB, IIIC, and IV melanoma that was not considered to be surgically resectable. Patients could have no more than 3 visceral metastases (not including lung metastases or nodal metastases associated with visceral organs), no visceral metastasis could be larger than 3 cm in diameter, and liver lesions had to be stable for at least 1 month.
Lactate dehydrogenase (LDH) could not be more than 1.5 x the upper limit of normal (ULN). In the Imlygic arm, 5% of patients had LDH levels > ULN. Patients with bone metastases or clinically active cerebral metastases, evidence of immunosuppression, patients receiving treatment with a systemic antiherpetic agent and patients with primary ocular or mucosal melanoma were also excluded.
A total of 436 patients were randomised in a 2:1 ratio to receive either Imlygic (n = 295) or GM-CSF (n = 141). Imlygic was administered by intralesional injection at an initial concentration of 106 (1 million) PFU/mL on day 1, followed by a concentration of 108 (100 million) PFU/mL on day 21 and every 2 weeks thereafter at a dose of up to 4 mL. GM-CSF was administered subcutaneously at 125 microgram/m2 delivered daily for 14 days followed by a 14 day rest period in repeating intervals.
The mean age was 63 (range: 22 to 94) years. Male patients comprised of 57% of study population and 70% of patients were baseline ECOG 0 performance status. Of the enrolled patients, 30% had stage III; 27% had stage IVM1a; 21% had stage IVM1b and 22% had stage IVM1c disease; 53% of patients had received prior therapy for melanoma (other than or in addition to surgery, adjuvant therapy, or radiation), and 58% were seropositive for wild type HSV-1 at baseline.
To allow for delayed immune mediated antitumour effects to occur, patients were treated for a minimum of 6 months or until no injectable lesions were remaining. During this period, treatment was to continue despite an increase in size of existing lesion(s) and/or development of new lesion(s) unless the patient's clinical condition required initiation of a new therapy. Patients experiencing a response at 12 months of treatment could continue treatment for up to an additional 6 months.
The primary endpoint was durable response rate (DRR) (defined as the percent of patients with complete response (CR) or partial response (PR) maintained continuously for a minimum of 6 months) per blinded central review using modified WHO criteria. The secondary endpoints included overall survival (OS), overall response rate (ORR) [PR + CR], time to response and duration of response. Treatment with Imlygic statistically significantly increased DRR in the overall population (Table 5).
There were 78 responders in the Imlygic arm and 8 in the GM-CSF arm. Among the Imlygic treated responders, 56 (72%) responses were still ongoing at the time of primary analysis. There was a 65% probability that responses lasted at least 12 months. Of the Imlygic responders, 42 (54%) experienced a ≥ 50% increase in overall size of existing lesion(s) and/or developed new lesion(s) prior to ultimately achieving a response.
In an analysis to evaluate systemic activity of Imlygic, 27 of 79 patients (34.2%) had a ≥ 50% overall decrease in nonvisceral lesions that were not injected with Imlygic and 8 of 71 patients (11.3%) had a ≥ 50% overall decrease in visceral lesions that were not injected with Imlygic. After treatment with Imlygic, 13 Imlygic treated patients underwent surgery with curative intent. Of these, 9 had no evidence of disease after surgery and 4 had a pathologic CR.
In the overall trial population, the median follow up time was 44.4 months and the median OS (95% CI) was 23.3 (19.5, 29.6) months and 18.9 (16.0, 23.7) months for Imlygic and GM-CSF, respectively (HR = 0.79; 95% CI: 0.62, 1.00; p = 0.051) (Figure 1). Among the Imlygic treated patients that achieved a durable response, there was a 96% probability of survival at 3 years.
The results for key study endpoints in the intent to treat population are summarised in Table 5.
Exploratory subgroup analyses for DRR, ORR and overall survival by stage of disease were also conducted (Table 6). The pivotal study was not powered to evaluate efficacy in these individual subgroups.

Supportive data in melanoma.

Study 2.

In the single arm open label phase 2 study investigating Imlygic, patients with stage IIIC or stage IV melanoma, were treated with up to 24 doses of Imlygic. Of the 50 patients enrolled, 14 (28%) achieved a response, 8 (16%) of which were CRs. Three patients received additional treatment with Imlygic in an optional extension study, in which one additional CR was observed resulting in a combined overall response rate of 30%. Of the 15 responses that occurred, eight were still ongoing at end of year 1 and two were ongoing at the end of year 2. The safety profile for patients in study 2 was comparable to that in study 1.

5.2 Pharmacokinetic Properties

Imlygic is a genetically modified and replication competent HSV-1 virus. Therefore, its pharmacokinetics and biodistribution are driven by the site of intralesional injection, tumour selective replication, and release from tumour tissue. None of the genetic modifications in Imlygic are expected to affect the absorption, metabolism, and elimination of Imlygic compared to wild type HSV-1. The biodistribution of Imlygic is consistent with tumour selective replication.

Absorption.

Cellular uptake of Imlygic occurs through HSV-1 receptors on tumours and nontumour cells following intralesional injection.

Distribution.

As Imlygic is injected and replicates intratumourally, neither bioavailability nor systemic concentration of Imlygic is predictive of drug activity.

Metabolism/excretion.

Imlygic is cleared through general host defence mechanisms (e.g. autophagy, adaptive immune responses). Imlygic is degraded by typical endogenous protein and DNA catabolic pathways. As with other wild type HSV-1 infections, a latent pool of Imlygic DNA may persist in neuronal cell bodies innervating the injection sites. The occurrence of latent infection with Imlygic has not been established in humans. However, in a mouse model, latency of Imlygic was observed and reactivation could be induced ex vivo.

Biodistribution (within the body) and viral shedding (excretion/secretion).

Imlygic (talimogene laherparepvec) DNA was quantified with a highly sensitive and specific quantitative polymerase chain reaction (qPCR) assay, which may not correlate with viral infectivity risk. Imlygic was also quantified in selected patient samples in clinical studies using viral infectivity assays at the injection sites and in some cases of potential herpetic lesions.

Nonclinical biodistribution, elimination, and shedding.

Following intralesional administration in mice, Imlygic DNA was detected in ~ 40% of tumour samples and in ≤ 20% of blood and organ tissue samples (e.g. spleen, lymph node, liver, heart and kidneys) in the 84 days following injection. Imlygic DNA was detected in ≤ 2% of samples of brain, ovary, and salivary gland, and was not detected in bone marrow, eyes, shedding tissues (lacrimal glands, nasal mucosa), or faeces. The concentrations of Imlygic DNA was generally highest in tumours and other tissues had lower levels of Imlygic DNA. Imlygic DNA could be found in injected tumours through 84 days after the last dose, but was cleared from the majority (94%) of blood samples by 7 days after the last dose. Following intravenous administration in mice, Imlygic DNA was quantifiable in ~ 17% of peripheral nerve (trigeminal ganglion) samples.

Clinical biodistribution, elimination, and shedding.

The biodistribution and shedding of intralesionally administered Imlygic are being investigated in a dedicated study. In results from 30 patients included in the interim analysis, Imlygic DNA was detected at transient and low concentrations in blood in 90% of individuals and in urine in 20% of individuals in the study. The proportion of individuals with detectable Imlygic DNA in blood and urine was highest during the second cycle of treatment. While approximately 90% of individuals had Imlygic DNA in samples obtained from the surface of injected lesions, only 14% of individuals tested positive for infective virus by TCID50 assay. Seventeen percent of samples from the exterior of occlusive dressing tested positive for Imlygic DNA but none tested positive for presence of infective virus. Among the 30 individuals tested for presence for Imlygic DNA in orolabial region, one individual had detectable Imlygic DNA, but the sample did not test positive for presence of infective virus.

Special populations.

Elderly.

The pharmacokinetic profile has not been assessed in the elderly.

Paediatric.

The pharmacokinetic profile has not been assessed in those ≤ 18 years.

Impaired renal function.

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

Impaired hepatic function.

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

5.3 Preclinical Safety Data

Genotoxicity.

The genotoxic potential of Imlygic has not been evaluated. Because wild type HSV-1 does not integrate into the host genome, the risk of insertional mutagenesis with Imlygic is negligible.

Carcinogenicity.

The carcinogenic potential of Imlygic has not been evaluated in long-term animal or human studies. However, available data for Imlygic and wild type HSV-1 do not indicate a carcinogenic risk in humans.

4 Clinical Particulars

4.1 Therapeutic Indications

Imlygic is indicated as monotherapy for the treatment of melanoma in patients with unresectable cutaneous, subcutaneous or nodal lesions after initial surgery.

4.3 Contraindications

Imlygic is contraindicated in patients:
with known hypersensitivity to talimogene laherparepvec or excipients (see Section 2 Qualitative and Quantitative Composition; Section 6.1 List of Excipients);
who are severely immunocompromised (e.g. patients with severe congenital or acquired cellular and/or humoral immune deficiency). These patients may be at risk for life threatening disseminated herpetic infection (see Section 4.4 Special Warnings and Precautions for Use).

4.4 Special Warnings and Precautions for Use

Immunocompromised patients.

Imlygic has not been studied in immunocompromised patients. Imlygic was injected into xenograft tumours at doses up to 2 x 108 PFU/kg (30-fold over the maximum clinical dose) in immunodeficient mice [nude and with severe combined immunodeficiency (SCID)]. Lethal systemic viral infection was observed in up to 20% of nude mice (primarily deficient in T lymphocyte function) and 100% of SCID mice (devoid of both T and B lymphocytes).
Based on the animal data, patients who are severely immunocompromised may be at an increased risk of disseminated herpetic infection and should not be treated with Imlygic (see Section 4.3 Contraindications). Disseminated herpetic infection may also occur in immunocompromised patients (such as those with HIV/AIDS, leukaemia, lymphoma, common variable immunodeficiency, or who require chronic high dose steroids or other immunosuppressive agents). Consider the risks and benefits of treatment before administering Imlygic to these patients.

Accidental exposure to Imlygic.

Accidental exposure may lead to transmission of Imlygic and herpetic infection. Healthcare providers, close contacts (household members, caregivers, sex partners or persons sharing the same bed) and pregnant women should avoid direct contact with injected lesions or body fluids of treated patients during the entirety of the treatment period and up to 30 days after the last treatment administration (see Section 5.2 Pharmacokinetic Properties). Healthcare providers who are immunocompromised should not administer Imlygic and should not come into direct contact with the Imlygic injection sites or body fluids of treated patients (see Section 4.2 Dose and Method of Administration). Accidental needle stick and splash back have been reported in healthcare providers during preparation and administration of Imlygic.
Patients should be advised to avoid touching or scratching injection sites as this could lead to inadvertent transfer of Imlygic to other areas of their body.
Although it is not known if Imlygic could be transmitted through sexual contact, it is known that wild type HSV-1 can be transmitted through sexual contact. Patients should be advised to use a latex condom during sexual contact to prevent possible transmission of Imlygic. Women of childbearing potential should be advised to use an effective method of contraception to prevent pregnancy during treatment with Imlygic (see Section 4.6 Fertility, Pregnancy and Lactation).
Close contacts who are pregnant or immunocompromised should not change the patient's dressings or clean their injection sites. Pregnant women, infants less than 3 months old, and immunocompromised individuals should not be exposed to potentially contaminated materials.
Caregivers should be advised to wear protective gloves and cover any exposed wounds when assisting patients in applying or changing occlusive dressings and to observe safety precautions for disposal of used dressings and cleaning materials (see Section 4.2 Dose and Method of Administration, Special instructions for use and handling).
In the event of an accidental exposure to Imlygic, exposed individuals should be advised to clean affected area thoroughly with soap and water and/or a disinfectant. If signs or symptoms of herpetic infection develop, they should contact their healthcare provider.

Neonatal exposure.

Infections with wild type HSV-1 in a foetus or neonate have been associated with serious adverse effects, including multiorgan failure and death (see Section 4.6 Fertility, Pregnancy and Lactation). While it is not known if Imlygic will behave like HSV-1, neonates should not be exposed to bodily fluids of the treated patient, injection site or contaminated materials. Neonatal herpetic infections have not been reported with Imlygic. If infection were to occur, contact a healthcare provider immediately.

Herpetic infection in Imlygic treated patients.

In clinical studies, herpetic infections (including cold sores and herpes keratitis) have been reported in patients treated with Imlygic. Symptoms of a local or systemic infection possibly related to Imlygic are anticipated to be similar to symptoms caused by wild type HSV-1 infections.
Individuals with wild type HSV-1 infection are known to be at a lifelong risk for symptomatic herpetic infection due to reactivation of latent wild type HSV-1.
Symptomatic herpetic infection due to possible reactivation of Imlygic should be considered.
Patients who develop herpetic infections should be advised to 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 (1800 803 638); patients or close contacts have the option of follow-up testing for further characterisation of the infection.
Imlygic is sensitive to aciclovir. Consider the risks and benefits of Imlygic treatment before administering aciclovir or other antiviral agents indicated for management of herpetic infection. These agents may interfere with the effectiveness of Imlygic.

Cellulitis at the injection site.

Necrosis or ulceration of tumour tissue may occur following Imlygic treatment. Cellulitis and systemic bacterial infection have been reported. Careful wound care and infection precautions are recommended, particularly if tissue necrosis results in open wounds.

Impaired healing at the injection site.

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).
Consider the risks and benefits of Imlygic before continuing treatment if persistent infection or delayed healing develops.

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.

Plasmacytoma has been reported in proximity to the injection site after administration of Imlygic. 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.

HSV-1 seronegative patients.

Patients who were HSV-1 seronegative at baseline were reported to have a greater incidence of pyrexia, chills, and influenza-like illness compared with those who were HSV-1 seropositive at baseline, especially during the first 3 months of treatment (see Section 4.8 Adverse Effects (Undesirable Effects)).

Use in the elderly.

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

Paediatric use.

The safety and efficacy of Imlygic have not been established in paediatric patients.

Effects on laboratory tests.

Interactions with laboratory tests have not been established.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No drug interactions studies have been conducted with Imlygic.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No nonclinical or clinical studies have been performed to evaluate the effects of Imlygic on fertility. There were no impacts to male or female reproductive tissues following treatment of adult mice at doses up to 4 x 108 (400 million) PFU/kg (60-fold higher, on a PFU/kg basis, compared to the maximum clinical dose).
(Category C)
Adequate and well controlled studies with Imlygic have not been conducted in pregnant women. No effects on embryofetal development have been observed in a study in mice.
If Imlygic is used during pregnancy, or if the patient becomes pregnant while taking Imlygic, the patient should be apprised of the potential hazards to the fetus and/or 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 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 multiorgan 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.
Transplacental metastases of malignant melanoma can occur. Because Imlygic is modified to enter and replicate in the tumour tissue, there could be a risk of fetal exposure to Imlygic from tumour tissue that has crossed the placenta. No effects on embryofetal development were observed when Imlygic was administered during organogenesis to pregnant mice at doses up to 4 x 108 (400 million) PFU/kg (60-fold higher, on a PFU/kg basis, compared to the maximum clinical dose). Negligible amounts (< 0.001% of maternal blood levels) of Imlygic DNA were found in fetal blood.
 It is not known whether Imlygic is transferred into human milk. The risk of possible transmission of Imlygic through lactation should be considered and patients should be advised to discontinue breastfeeding or to discontinue Imlygic prior to breastfeeding.

4.8 Adverse Effects (Undesirable Effects)

Summary of safety profile.

The safety of Imlygic was evaluated in 419 patients (292 Imlygic, 127 GM-CSF) in study 1 that received at least 1 dose of study treatment.
The median duration of exposure to Imlygic was 23 weeks (5.3 months). Twenty six patients were exposed to Imlygic for at least one year.

Tabulated list of adverse events.

Table 3 lists adverse events reported in Study 1.

Adverse reactions.

The most commonly reported adverse reactions (≥ 25%) in Imlygic treated patients were fatigue, chills, pyrexia, nausea, influenza like illness, and injection site pain. Ninety eight percent of these adverse reactions reported were mild or moderate in severity. The most common grade 3 or higher adverse reaction was cellulitis (see Section 4.4 Special Warnings and Precautions for Use).
Safety data obtained from 50 patients in study 2 and extension studies were consistent with data from study 1. Adverse reactions observed in Imlygic clinical trials are listed in Table 4 by frequency and MedDRA body system organ class.

Description of selected adverse reactions.

Influenza-like symptoms.

Pyrexia, chills, and influenza-like illness, which can occur anytime during Imlygic treatment, generally resolved within 72 hours. These events were reported more frequently during the first 3 cycles of treatment, particularly in patients who were HSV-1 negative at baseline.

Post-marketing experience.

The following adverse reactions have been identified during post approval use of Imlygic.
Hypersensitivity; granulomatous dermatitis; dyspnoea.

Reporting of suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at https://www.tga.gov.au/reporting-problems.

4.2 Dose and Method of Administration

Dosage (dose and interval).

Imlygic is administered by intralesional injection into cutaneous, subcutaneous, and/or nodal lesions that are visible, palpable, or detectable by ultrasound guidance.

Recommended dose and schedule.

The total injection volume for each treatment visit should be up to a maximum of 4 mL. The initial recommended dose is up to a maximum of 4 mL of Imlygic at a concentration of 106 (1 million) PFU/mL. Subsequent doses should be administered up to 4 mL of Imlygic at a concentration of 108 (100 million) PFU/mL. The same lesion(s) may be injected in more than one treatment visit. The recommended dosing schedule for Imlygic is shown in Table 1.

Determining Imlygic dose volume per lesion.

The volume of Imlygic to be injected into each lesion is dependent on the size of the lesion and should be determined according to Table 2.
Since patients may experience increase in size of existing lesions or the appearance of new lesion(s) prior to achieving a response, Imlygic treatment should be continued where there is opportunity for clinical benefit unless other treatment is required or until no injectable lesions are remaining.
Imlygic treatment may be reinitiated if new lesion(s) appear following a complete response.

Method of administration.

Healthcare providers should avoid accidental exposure to Imlygic and follow handling instructions while administering the medicine (see Section 4.2 Dose and Method of Administration, Special instructions for use and handling).
Healthcare providers who are immunocompromised should not administer Imlygic and should not come into direct contact with the Imlygic injection sites or body fluids of treated patients (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).
Follow the instructions below to prepare and administer Imlygic to patients.

Preinjection.

Thaw Imlygic vials at room temperature (see Section 6.3 Shelf Life).
Draw desired amount of Imlygic from the vial into a syringe. A 22 to 24 gauge needle is recommended.
The injection site may be treated with a topical anaesthetic agent. Injectable anaesthetic may be injected around the periphery of the lesion, but should not be injected directly into the lesion.
Clean the lesion and surrounding areas with an alcohol swab and let dry.

Injection.

Imlygic does not contain any antimicrobial preservative or bacteriostatic agent. To reduce microbiological hazard, Imlygic should not be drawn into a syringe until immediately prior to administration.
Inject Imlygic intralesionally into cutaneous, subcutaneous, and/or nodal lesions that are visible, palpable, or detectable by ultrasound guidance.
Determine injection volume for each lesion using Table 2.
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.
Disperse 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 or splash back of Imlygic at the insertion point.
Repeat these steps for other lesions that need to be injected. Use a new needle anytime the needle is completely removed from a lesion and each time a different lesion is injected.

Postinjection.

Apply pressure to the injection site with sterile gauze for at least 30 seconds.
Swab the injection site and surrounding area with alcohol and cover the injected lesion with an absorbent pad and dry occlusive dressing.

Special instructions for use and handling.

Follow local institutional guidelines for handling and administration, personal protective equipment, accidental spills, and waste disposal.
Wear protective gown or laboratory coat, safety glasses or face shield and gloves while preparing or administering Imlygic. Cover any exposed wounds before administering. Avoid contact with skin, eyes or mucous membranes.
After administration, change gloves prior to applying occlusive dressings to injected lesions. Wipe the exterior of occlusive dressing with an alcohol wipe and advise patients to keep the injection sites covered at all times and replace dressing if it falls off.
Dispose of all materials that have come in contact with Imlygic (e.g. vial, syringe, needle, any cotton or gauze) in accordance with local institutional procedures.
In the event of an accidental occupational exposure to Imlygic (e.g. through a splash to the eyes or mucous membranes) during preparation or administration, 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 disinfectant.
Treat all Imlygic spills with a virucidal agent and absorbent materials.
Advise patients to place used dressings and cleaning materials in a sealed plastic bag and dispose in household waste.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effect on the ability to drive or use heavy machinery have been performed in patients receiving Imlygic.

4.9 Overdose

There is no clinical experience with overdosage with Imlygic. Doses up to 4 mL at a concentration of 108 PFU/mL every 2 weeks have been administered in clinical trials 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.
For advice on the management of overdose contact the Poisons Information Centre on 131126.

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Each single-use vial of Imlygic contains: 15.4 mg dibasic sodium phosphate dihydrate, 2.44 mg monobasic sodium phosphate dihydrate, 8.5 mg sodium chloride, 40.0 mg inositol, 20 mg sorbitol, water for injections.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.
Imlygic should be thawed prior to administration. See thawing instructions below.

Thawing Imlygic vials.

Imlygic vials should be thawed and stored in the original carton until preparation for administration.
Before use, thaw frozen Imlygic vials at room temperature (20°C to 25°C) until Imlygic is liquid (approximately 30 minutes). Gently swirl. Do not shake.

After thawing.

After thawing, administer Imlygic as soon as practically feasible.
Thawed Imlygic is stable when stored at temperatures of 2°C up to 25°C protected from light in its original vial, in a syringe, or in the original vial followed by a syringe. Do not exceed the storage times specified in Table 7 and Table 8.
If storing thawed Imlygic in the original vial followed by a syringe:
the same temperature range should be maintained throughout the duration of storage until administration;
the storage time in the syringe at ambient temperature up to 25°C cannot exceed 2 hours for 106 (1 million) PFU/mL and 4 hours for 108 (100 million) PFU/mL (see Table 7);
the maximum cumulative storage time (storage time in vial plus storage time in syringe) cannot exceed the durations in Table 8.
Imlygic must not be refrozen once it has thawed. Discard any thawed Imlygic in the vial or syringe stored longer than the specified times in Tables 7 and 8.

6.4 Special Precautions for Storage

Imlygic must be transported and stored at -90°C to -70°C.
Imlygic should be protected from light.
Imlygic should be stored in the carton until use.

6.5 Nature and Contents of Container

Imlygic is provided as a 1 mL sterile, single-use, preservative-free frozen liquid in a cyclic olefin polymer (COP) plastic resin vial with a chlorobutyl elastomer stopper, aluminium seal, and polypropylene cap in two different presentations:
Single-use vial permanently inserted into a clear copolyester plastic sleeve or single-use vial without a clear plastic sleeve.
The vial cap is colour coded:
106 (1 million) PFU/mL - For initial dose only - is light green.
108 (100 million) PFU/mL - For all subsequent doses - is royal blue.

6.6 Special Precautions for Disposal

Dispose of all materials that have come in contact with Imlygic (e.g. vial, syringe, needle, any cotton or gauze) in accordance with local institutional procedures (see Section 4.2 Dose and Method of Administration, Special instructions for use and handling).

Summary Table of Changes