YERVOY Concentrate for solution for infusion Ref.[8371] Active ingredients: Ipilimumab

Treatment must be initiated and supervised by specialist physicians experienced in the treatment of cancer.

PD-L1 testing

If specified in the indication, patient selection for treatment with YERVOY based on the tumour expression of PD-L1 should be confirmed by a validated test (see sections 4.1, 4.4, and 5.1).

Posology

YERVOY as monotherapy

Melanoma

Adults and adolescents 12 years of age and older:

The recommended induction regimen of YERVOY is 3 mg/kg administered intravenously over a 90-minute period every 3 weeks for a total of 4 doses. Patients should receive the entire induction regimen (4 doses) as tolerated, regardless of the appearance of new lesions or growth of existing lesions. Assessments of tumour response should be conducted only after completion of induction therapy.

YERVOY in combination with nivolumab

Melanoma

In adults and adolescents 12 years of age and older and weighing at least 50 kg, the recommended dose is 3 mg/kg ipilimumab in combination with 1 mg/kg nivolumab administered intravenously every 3 weeks for the first 4 doses. This is then followed by a second phase in which nivolumab monotherapy is administered intravenously at either 240 mg every 2 weeks or at 480 mg every 4 weeks (see sections 5.1 and 5.2), as presented in Table 1. For the monotherapy phase, the first dose of nivolumab should be administered:

• 3 weeks after the last dose of the combination of nivolumab and ipilimumab if using 240 mg every 2 weeks; or
• 6 weeks after the last dose of the combination of nivolumab and ipilimumab if using 480 mg every 4 weeks.

In adolescents 12 years of age and older and weighing less than 50 kg, the recommended dose is 3 mg/kg ipilimumab in combination with 1 mg/kg nivolumab administered intravenously every 3 weeks for the first 4 doses. This is then followed by a second phase in which nivolumab monotherapy is administered intravenously at either 3 mg/kg every 2 weeks or 6 mg/kg every 4 weeks 4 (see sections 5.1 and 5.2), as presented in Table 1. For the monotherapy phase, the first dose of nivolumab should be administered:

• 3 weeks after the last dose of the combination of nivolumab and ipilimumab if using 3 mg/kg every 2 weeks; or
• 6 weeks after the last dose of the combination of nivolumab and ipilimumab if using 6 mg/kg every 4 weeks.

Table 1. Recommended doses and infusion times for intravenous administration of ipilimumab in combination with nivolumab:

Renal cell carcinoma and dMMR or MSI-H colorectal cancer

The recommended dose is 1 mg/kg ipilimumab in combination with 3 mg/kg nivolumab administered intravenously every 3 weeks for the first 4 doses. This is then followed by a second phase in which nivolumab monotherapy is administered intravenously at either 240 mg every 2 weeks or at 480 mg every 4 weeks (RCC only), as presented in Table 2. For the monotherapy phase, the first dose of nivolumab should be administered;

• 3 weeks after the last dose of the combination of ipilimumab and nivolumab if using 240 mg every 2 weeks; or
• 6 weeks after the last dose of the combination of ipilimumab and nivolumab if using 480 mg every 4 weeks (RCC only).

Table 2. Recommended doses and infusion times for intravenous administration of ipilimumab in combination with nivolumab for RCC and dMMR or MSI-H CRC:

Malignant pleural mesothelioma

The recommended dose is 1 mg/kg ipilimumab administered intravenously over 30 minutes every 6 weeks in combination with 360 mg nivolumab administered intravenously over 30 minutes every 3 weeks. Treatment is continued for up to 24 months in patients without disease progression.

Oesophageal squamous cell carcinoma

The recommended dose is 1 mg/kg ipilimumab administered intravenously over 30 minutes every 6 weeks in combination with either 3 mg/kg nivolumab every 2 weeks or 360 mg nivolumab every 3 weeks administered intravenously over 30 minutes. Treatment is recommended until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

YERVOY in combination with nivolumab and chemotherapy

Non-small cell lung cancer

The recommended dose is 1 mg/kg ipilimumab administered intravenously over 30 minutes every 6 weeks in combination with 360 mg nivolumab administered intravenously over 30 minutes every 3 weeks, and platinum-based chemotherapy administered every 3 weeks. After completion of 2 cycles of chemotherapy, treatment is continued with 1 mg/kg ipilimumab every 6 weeks in combination with 360 mg nivolumab administered intravenously every 3 weeks. Treatment is recommended until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Duration of treatment

Treatment with YERVOY in combination with nivolumab, should be continued as long as clinical benefit is observed or until treatment is no longer tolerated by the patient (and up to maximum duration of therapy if specified for an indication).

Atypical responses (i.e., an initial transient increase in tumour size or small new lesions within the first few months followed by tumour shrinkage) have been observed. It is recommended to continue treatment with YERVOY in combination with nivolumab for clinically stable patients with initial evidence of disease progression until disease progression is confirmed.

Liver function tests (LFTs) and thyroid function tests should be evaluated at baseline and before each dose of YERVOY. In addition, any signs or symptoms of immune-related adverse reactions, including diarrhoea and colitis, must be assessed during treatment with YERVOY (see Tables 3A, 3B, and section 4.4).

Children younger than 12 years of age

The safety and efficacy of ipilimumab in children younger than 12 years of age has not been established.

Permanent discontinuation of treatment or withholding of doses

Management of immune-related adverse reactions may require withholding of a dose or permanent discontinuation of YERVOY therapy and institution of systemic high-dose corticosteroid. In some cases, addition of other immunosuppressive therapy may be considered (see section 4.4).

Dose escalation or reduction is not recommended. Dosing delay or discontinuation may be required based on individual safety and tolerability.

Guidelines for permanent discontinuation or withholding of doses are described in Tables 3A and 3B for YERVOY as monotherapy, and in Table 3C for YERVOY in combination with nivolumab or administration of the second phase of treatment (nivolumab monotherapy) following combination treatment. Detailed guidelines for the management of immune-related adverse reactions are described in section 4.4.

Table 3A. When to permanently discontinue YERVOY as monotherapy:

^a Toxicity grades are in accordance with National Cancer Institute Common Terminology Criteria for Adverse Events. Version 4.0 (NCI-CTCAE v4).
^b Any other adverse reactions that are demonstrated or suspected to be immune-related should be graded according to CTCAE. Decision whether to discontinue YERVOY should be based on severity.
^c Patients with severe (Grade 3 or 4) endocrinopathy controlled with hormone replacement therapy may remain on therapy.

Table 3B. When to withhold dose of YERVOY as monotherapy:

^a No dose reduction of YERVOY is recommended.
^b Toxicity grades are in accordance with National Cancer Institute Common Terminology Criteria for Adverse Events. Version 4.0 (NCI-CTCAE v4).
^c Any other organ system adverse reactions that are considered immune-related should be graded according to CTCAE. Decision whether to withhold a dose should be based on severity.
^d Until administration of all 4 doses or 16 weeks from first dose, whichever occurs earlier.

Table 3C. Recommended treatment modifications for YERVOY in combination with nivolumab or administration of the second phase of treatment (nivolumab monotherapy) following combination treatment:

Note: Toxicity grades are in accordance with National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v4).
^a Recommendation for the use of hormone replacement therapy is provided in section 4.4.
^b The safety of re-initiating ipilimumab in combination with nivolumab therapy in patients previously experiencing immune-related myocarditis is not known.

YERVOY in combination with nivolumab should be permanently discontinued for:

• Grade 4 or recurrent Grade 3 adverse reactions;
• Persistent Grade 2 or 3 adverse reactions despite management.

When YERVOY is administered in combination with nivolumab, if either agent is withheld, the other agent should also be withheld. If dosing is resumed after a delay, either the combination treatment or nivolumab monotherapy could be resumed based on the evaluation of the individual patient.

Special populations

Paediatric population

The safety and efficacy of YERVOY as monotherapy in children younger than 12 years of age have not been established. Very limited data are available. YERVOY should not be used in children younger than 12 years of age.

The safety and efficacy of YERVOY in combination with nivolumab in children younger than 18 years of age have not been established, except in adolescents 12 years of age and older with melanoma. Currently available data are described in sections 4.2, 4.8, 5.1 and 5.2.

Elderly

No overall differences in safety or efficacy were reported between elderly (≥65 years) and younger patients (<65 years). Data from first-line RCC patients 75 years of age or older are too limited to draw conclusions on this population (see section 5.1). No specific dose adjustment is necessary in this population (see section 5.1).

Renal impairment

The safety and efficacy of YERVOY have not been studied in patients with renal impairment. Based on population pharmacokinetic results, no specific dose adjustment is necessary in patients with mild to moderate renal dysfunction (see section 5.2).

Hepatic impairment

The safety and efficacy of YERVOY have not been studied in patients with hepatic impairment. Based on the population pharmacokinetic results, no specific dose adjustment is necessary in patients with mild hepatic impairment (see section 5.2). YERVOY must be administered with caution in patients with transaminase levels ≥5 x ULN or bilirubin levels >3 x ULN at baseline (see section 5.1).

Method of administration

YERVOY is for intravenous use. The recommended infusion period is 30 minutes.

YERVOY can be used for intravenous administration without dilution or may be diluted in sodium chloride 9 mg/ml (0.9%) solution for injection or glucose 50 mg/ml (5%) solution for injection to concentrations between 1 and 4 mg/ml.

YERVOY must not be administered as an intravenous push or bolus injection.

When administered in combination with nivolumab or in combination with nivolumab and chemotherapy, nivolumab should be given first followed by YERVOY and then by chemotherapy (if applicable) on the same day. Use separate infusion bags and filters for each infusion.

For instructions on the preparation and handling of the medicinal product before administration, see section 6.6.

The maximum tolerated dose of ipilimumab has not been determined. In clinical trials, patients received up to 20 mg/kg without apparent toxic effects.

In case of overdose, patients must be closely monitored for signs or symptoms of adverse reactions, and appropriate symptomatic treatment instituted.

Unopened vial:

3 years.

After opening:

From a microbiological point of view, once opened, the medicinal product should be infused or diluted and infused immediately. The chemical and physical in-use stability of the undiluted or diluted concentrate (between 1 and 4 mg/ml) has been demonstrated for 24 hrs at 25°C and 2°C to 8°C. If not used immediately, the infusion solution (undiluted or diluted) may be stored for up to 24 hours in a refrigerator (2°C to 8°C) or at room temperature (20°C to 25°C).

Store in a refrigerator (2°C-8°C).

Do not freeze.

Store in the original package in order to protect from light.

For storage conditions after first opening or dilution of the medicinal product, see section 6.3.

10 ml of concentrate in a vial (Type I glass) with a stopper (coated butyl rubber) and a flip-off seal (aluminium). Pack size of 1.

40 ml of concentrate in a vial (Type I glass) with a stopper (coated butyl rubber) and a flip-off seal (aluminium). Pack size of 1.

Not all pack sizes may be marketed.

Preparation should be performed by trained personnel in accordance with good practices rules, especially with respect to asepsis.

Calculating the dose

Ipilimumab monotherapy or ipilimumab in combination with nivolumab:

The prescribed dose for the patient is given in mg/kg. Based on this prescribed dose, calculate the total dose to be given. More than one vial of YERVOY concentrate may be needed to give the total dose for the patient.

• Each 10 ml vial of YERVOY concentrate provides 50 mg of ipilimumab; each 40 ml vial provides 200 mg of ipilimumab.
• The total ipilimumab dose in mg = the patient’s weight in kg × the prescribed dose in mg/kg.
• The volume of YERVOY concentrate to prepare the dose (ml) = the total dose in mg, divided by 5 (the YERVOY concentrate strength is 5 mg/ml).

Preparing the infusion

Take care to ensure aseptic handling when you prepare the infusion.

YERVOY can be used for intravenous administration either:

• without dilution, after transfer to an infusion container using an appropriate sterile syringe; or
• after diluting to up to 5 times the original volume of concentrate (up to 4 parts of diluent to 1 part of concentrate). The final concentration should range from 1 to 4 mg/ml. To dilute the YERVOY concentrate, you can use either:
  • sodium chloride 9 mg/ml (0.9%) solution for injection; or
  • 50 mg/ml (5%) glucose solution for injection

STEP 1:

• Allow the appropriate number of vials of YERVOY to stand at room temperature for approximately 5 minutes.
• Inspect the YERVOY concentrate for particulate matter or discoloration. YERVOY concentrate is a clear to slightly opalescent, colourless to pale yellow liquid that may contain light (few) particulates. Do not use if unusual amount of particles and signs of discoloration are present.
• Withdraw the required volume of YERVOY concentrate using an appropriate sterile syringe.

STEP 2:

• Transfer the concentrate into a sterile, evacuated glass bottle or intravenous bag (PVC or non-PVC).
• If applicable, dilute with the required volume of sodium chloride 9 mg/ml (0.9%) solution for injection or 50 mg/ml (5%) glucose solution for injection. For ease of preparation, the concentrate can also be transferred directly into a pre-filled bag containing the appropriate volume of sodium chloride 9 mg/mL (0.9%) solution for injection or 50 mg/mL (5%) glucose solution for injection. Gently mix the infusion by manual rotation.

Administration

The YERVOY infusion must not be administered as an intravenous push or bolus injection. Administer the YERVOY infusion intravenously over a period of 30 or 90 minutes, depending on the dose.

The YERVOY infusion should not be infused at the same time in the same intravenous line with other agents. Use a separate infusion line for the infusion.

Use an infusion set and an in-line, sterile, non-pyrogenic, low protein binding filter (pore size of 0.2 μm to 1.2 μm).

The YERVOY infusion is compatible with:

• PVC infusion sets
• Polyethersulfone (0.2 μm to 1.2 μm) and nylon (0.2 μm) in-line filters

Flush the line with sodium chloride 9 mg/ml (0.9%) solution for injection or 50 mg/ml (5%) glucose solution for injection at the end of the infusion.

Any unused medicinal product or waste material should be discarded in accordance with local requirements.