OPDIVO Concentrate for solution for infusion Ref.[7411] Active ingredients: Nivolumab

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

Posology

OPDIVO as monotherapy

The recommended dose of OPDIVO is either nivolumab 240 mg every 2 weeks or 480 mg every 4 weeks (see section 5.1) depending on the indication, as presented in Table 1.

Table 1. Recommended dose and infusion time for intravenous administration of nivolumab monotherapy:

* As per monotherapy indication in section 4.1.

If melanoma or RCC patients need to be switched from the 240 mg every 2 weeks schedule to the 480 mg every 4 weeks schedule, the first 480 mg dose should be administered two weeks after the last 240 mg dose. Conversely, if patients need to be switched from the 480 mg every 4 weeks schedule to the 240 mg every 2 weeks schedule, the first 240 mg dose should be administered four weeks after the last 480 mg dose.

Adjuvant treatment of melanoma

The recommended dose of OPDIVO is 3 mg/kg nivolumab administered intravenously over 60 minutes every 2 weeks.

For adjuvant therapy, the maximum treatment duration with OPDIVO is 12 months.

OPDIVO in combination with ipilimumab

Melanoma

The recommended dose is 1 mg/kg nivolumab in combination with 3 mg/kg ipilimumab 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, 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 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.

Table 2. Recommended doses and infusion times for intravenous administration of nivolumab in combination with ipilimumab:

Renal Cell Carcinoma

The recommended dose is 3 mg/kg nivolumab in combination with 1 mg/kg ipilimumab 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, as presented in Table 3. 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.

Table 3. Recommended doses and infusion times for intravenous administration of nivolumab in combination with ipilimumab:

Treatment with OPDIVO, either as a monotherapy or in combination with ipilimumab, should be continued as long as clinical benefit is observed or until treatment is no longer tolerated by the patient.

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 nivolumab or nivolumab in combination with ipilimumab for clinically stable patients with initial evidence of disease progression until disease progression is confirmed.

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 Table 4. Detailed guidelines for the management of immune-related adverse reactions are described in section 4.4.

Table 4. Recommended treatment modifications for OPDIVO or OPDIVO in combination with ipilimumab:

OPDIVO or OPDIVO in combination with ipilimumab should be permanently discontinued for:

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

Patients treated with OPDIVO must be given the patient alert card and be informed about the risks of OPDIVO (see also package leaflet).

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

Special populations

Paediatric population

The safety and efficacy of OPDIVO in children below 18 years of age have not been established. No data are available.

Elderly

No dose adjustment is required for elderly patients (≥65 years) (see section 5.2).

Data from SCCHN, adjuvant melanoma and first-line RCC patients 75 years of age or older are too limited to draw conclusions on this population (see sections 4.8 and 5.1).

Renal impairment

Based on the population pharmacokinetic (PK) results, no dose adjustment is required in patients with mild or moderate renal impairment (see section 5.2). Data from patients with severe renal impairment are too limited to draw conclusions on this population.

Hepatic impairment

Based on the population PK results, no dose adjustment is required in patients with mild hepatic impairment (see section 5.2). Data from patients with moderate or severe hepatic impairment are too limited to draw conclusions on these populations. OPDIVO must be administered with caution in patients with moderate (total bilirubin >1.5 × to 3 × the upper limit of normal [ULN] and any AST) or severe (total bilirubin >3 × ULN and any AST) hepatic impairment.

Method of administration

OPDIVO is for intravenous use only. It is to be administered as an intravenous infusion over a period of 30 or 60 minutes depending on the dose (see Tables 1, 2 and 3). The infusion must be administered through a sterile, non-pyrogenic, low protein binding in-line filter with a pore size of 0.2-1.2 μm.

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

The total dose of OPDIVO required can be infused directly as a 10 mg/mL solution or can be diluted with sodium chloride 9 mg/mL (0.9%) solution for injection or glucose 50 mg/mL (5%) solution for injection (see section 6.6).

When administered in combination with ipilimumab, OPDIVO should be given first followed by ipilimumab 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.

No cases of overdose have been reported in clinical trials. In case of overdose, patients should be closely monitored for signs or symptoms of adverse reactions, and appropriate symptomatic treatment instituted immediately.

Shelf life

Unopened vial:

40 mg/4 mL and 100 mg/10 mL vials: 3 years.

240 mg/24 mL vial: 2 years.

After opening:

From a microbiological point of view, once opened, the medicinal product should be infused or diluted and infused immediately.

After preparation of infusion:

From a microbiological point of view, the product should be used immediately. If not used immediately, chemical and physical in-use stability of OPDIVO has been demonstrated for 24 hours at 2°C to 8°C protected from light and a maximum of 8 hours at 20°C-25°C and room light (this 8-hour period of the total 24 hours should be inclusive of the product administration period).

Store in a refrigerator (2°C-8°C).

Do not freeze.

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

The unopened vial can be stored at controlled room temperature up to 25°C with room light for up to 48 hours.

For storage conditions after preparation of the infusion, see section 6.3.

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

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

24 mL of concentrate in a 25 mL vial (Type I glass) with a stopper (coated butyl rubber) and a red matte flip-off seal (aluminium). Pack size of 1 vial.

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.

Preparation and administration

Calculating the dose

More than one vial of OPDIVO concentrate may be needed to give the total dose for the patient.

Nivolumab monotherapy: The prescribed dose for the patient is 240 mg or 480 mg given regardless of body weight depending on indication (see section 4.2).

Nivolumab monotherapy (for the adjuvant treatment of melanoma) or nivolumab in combination with ipilimumab:

The prescribed dose for the patient is given in mg/kg. Based on this prescribed dose, calculate the total dose to be given.

• The total nivolumab dose in mg = the patient’s weight in kg × the prescribed dose in mg/kg.
• The volume of OPDIVO concentrate to prepare the dose (mL) = the total dose in mg, divided by 10 (the OPDIVO concentrate strength is 10 mg/mL).

Preparing the infusion

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

OPDIVO can be used for intravenous administration either:

• without dilution, after transfer to an infusion container using an appropriate sterile syringe; or
• after diluting according to the following instructions:
  • the final infusion concentration should range between 1 and 10 mg/mL.
  • the total volume of infusion must not exceed 160 mL. For patients weighing less than 40 kg, the total volume of infusion must not exceed 4 mL per kilogram of patient weight.

OPDIVO concentrate may be diluted with either:

• sodium chloride 9 mg/mL (0.9%) solution for injection; or
• 50 mg/mL (5%) glucose solution for injection.

STEP 1:

*Inspect the OPDIVO concentrate for particulate matter or discoloration. Do not shake the vial. OPDIVO concentrate is a clear to opalescent, colourless to pale yellow liquid. Discard the vial if the solution is cloudy, is discoloured, or contains particulate matter other than a few translucent-to-white particles.

• Withdraw the required volume of OPDIVO concentrate using an appropriate sterile syringe.

STEP 2:

• Transfer the concentrate into a sterile, evacuated glass bottle or intravenous container (PVC or polyolefin).
• 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. Do not shake.

Administration

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

Administer the OPDIVO infusion intravenously over a period of 30 or 60 minutes depending on the dose.

OPDIVO 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).

OPDIVO infusion is compatible with PVC and polyolefin containers, glass bottles, PVC infusion sets and in-line filters with polyethersulfone membranes with pore sizes of 0.2 μm to 1.2 μm.

After administration of the nivolumab dose, flush the line with sodium chloride 9 mg/mL (0.9%) solution for injection or 50 mg/mL (5%) glucose solution for injection.

Disposal

Do not store any unused portion of the infusion solution for reuse. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.