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.

PD-L1 testing

If specified in the indication, patient selection for treatment with OPDIVO 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

OPDIVO as monotherapy

The recommended dose of OPDIVO is either nivolumab 240 mg every 2 weeks or 480 mg every 4 weeks depending on the indication and population (see sections 5.1 and 5.2), 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, RCC, OC, GEJC or MIUC (adjuvant treatment) 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.

OPDIVO in combination with ipilimumab

Melanoma

In adults and adolescents 12 years of age and older and weighing at least 50 kg, 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 (see sections 5.1 and 5.2), 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.

In adolescents 12 years of age and older and weighing less than 50 kg, 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 3 mg/kg every 2 weeks or 6 mg/kg every 4 weeks (see sections 5.1 and 5.2), 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 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 2. Recommended doses and infusion times for intravenous administration of nivolumab in combination with ipilimumab for melanoma:

Malignant pleural mesothelioma

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

Renal cell carcinoma and dMMR or MSI-H colorectal cancer

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 (RCC only), 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 (RCC only).

Table 3. Recommended doses and infusion times for intravenous administration of nivolumab in combination with ipilimumab for RCC and dMMR or MSI-H CRC:

Oesophageal squamous cell carcinoma

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

OPDIVO in combination with cabozantinib

Renal cell carcinoma

The recommended dose is nivolumab administered intravenously at either 240 mg every 2 weeks or 480 mg every 4 weeks in combination with 40 mg cabozantinib administered orally every day.

Table 4. Recommended doses and infusion times for intravenous administration of nivolumab in combination with oral administration of cabozantinib for RCC:

OPDIVO in combination with ipilimumab and chemotherapy

Non-small cell lung cancer

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

OPDIVO in combination with chemotherapy

Non-small cell lung cancer

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

OPDIVO in combination with chemotherapy

Neoadjuvant treatment of non-small cell lung cancer

The recommended dose is 360 mg nivolumab administered intravenously over 30 minutes in combination with platinum-based chemotherapy every 3 weeks for 3 cycles (see section 5.1).

Oesophageal squamous cell carcinoma

The recommended dose of nivolumab is 240 mg every 2 weeks or 480 mg every 4 weeks administered intravenously over 30 minutes in combination with fluoropyrimidine- and platinum-based chemotherapy (see section 5.1). Treatment with nivolumab is recommended until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Gastric, gastro-oesophageal junction or oesophageal adenocarcinoma

The recommended dose is 360 mg nivolumab administered intravenously over 30 minutes in combination with fluoropyrimidine- and platinum-based chemotherapy administered every 3 weeks or 240 mg nivolumab administered intravenously over 30 minutes in combination with fluoropyrimidineand platinum-based chemotherapy administered every 2 weeks (see section 5.1). Treatment with nivolumab is recommended until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

First-line treatment of unresectable or metastatic urothelial carcinoma

The recommended dose is 360 mg nivolumab administered intravenously over 30 minutes in combination with cisplatin and gemcitabine every 3 weeks for up to 6 cycles followed by nivolumab monotherapy administered intravenously at either 240 mg every 2 weeks over 30 minutes or at 480 mg every 4 weeks over 30 minutes (see section 5.1). Treatment with nivolumab is recommended until disease progression, unacceptable toxicity, or up to 24 months from first dose, whichever comes first.

Duration of treatment

Treatment with OPDIVO, either as a monotherapy or in combination with ipilimumab or other therapeutic agents, 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).

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

For OPDIVO in combination with cabozantinib, OPDIVO should be continued until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression. Cabozantinib should be continued until disease progression or unacceptable toxicity. Refer to the Summary of Product Characteristics (SmPC) for cabozantinib.

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 for OPDIVO as monotherapy or in combination with other therapeutic agents. 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 5. Detailed guidelines for the management of immune-related adverse reactions are described in section 4.4. When nivolumab is administered in combination with other therapeutic agents, refer to the SmPC of these other combination therapeutic agents regarding dosing.

Table 5. Recommended treatment modifications for OPDIVO or OPDIVO in combination:

Note: Toxicity grades are in accordance with National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v4).
^a During administration of the second phase of treatment (nivolumab monotherapy) following combination treatment, permanently discontinue treatment if Grade 3 diarrhoea or colitis occurs.
^b Recommendation for the use of hormone replacement therapy is provided in section 4.4.
^c The safety of re-initiating nivolumab or nivolumab in combination with ipilimumab therapy in patients previously.

OPDIVO as monotherapy or in combination with other therapeutic agents 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.

When OPDIVO is administered in combination with chemotherapy, refer to the SmPC of the other combination therapy agents regarding dosing. If any agents are withheld, the other agents may be continued. If dosing is resumed after a delay, either the combination treatment, OPDIVO monotherapy or chemotherapy alone could be resumed based on the evaluation of the individual patient.

OPDIVO in combination with cabozantinib in RCC

When OPDIVO is used in combination with cabozantinib, the above treatment modifications in Table 5 also apply to the OPDIVO component. In addition, for liver enzyme elevations, in patients with RCC being treated with OPDIVO in combination with cabozantinib:

• If ALT or AST >3 times ULN but ≤ 10 times ULN without concurrent total bilirubin ≥2 times ULN, both OPDIVO and cabozantinib should be withheld until these adverse reactions recover to Grades 0-1. Corticosteroid therapy may be considered. Rechallenge with a single medicine or rechallenge with both medicines after recovery may be considered. If rechallenging with cabozantinib, refer to cabozantinib SmPC.
• If ALT or AST >10 times ULN or >3 times ULN with concurrent total bilirubin ≥2 times ULN, both OPDIVO and cabozantinib should be permanently discontinued and corticosteroid therapy may be considered.

Special populations

Paediatric population

The safety and efficacy of OPDIVO in children below 18 years of age have not been established except in adolescents 12 years of age and older with melanoma. Currently available data of OPDIVO as monotherapy or in combination with ipilimumab are described in sections 4.2, 4.8, 5.1 and 5.2.

Elderly

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

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, 3 and 4). 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 and/or chemotherapy, OPDIVO should be given first followed by ipilimumab (if applicable) and then by chemotherapy 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.

Unopened vial:

3 years.

After preparation of infusion:

Chemical and physical in-use stability from the time of preparation has been demonstrated as follows (times are inclusive of the administration period):

From a microbiological point of view the prepared solution for infusion, regardless of the diluent, should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 7 days at 2°C to 8°C or 8 hours (of the total 7 days of storage) at room temperature (≤25°C). Aseptic handling should be ensured during the preparation of infusion (see section 6.6).

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.

12 mL of concentrate in a 25 mL vial (Type I glass) with a stopper (coated butyl rubber) and a blue 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 adult patient is 240 mg or 480 mg given regardless of body weight depending on indication (see section 4.2).

Melanoma (advanced or adjuvant treatment) in adolescents. The prescribed dose for adolescents 12 years of age and older weighing at least 50 kg is 240 mg or 480 mg. For adolescents 12 years of age and older and weighing less than 50 kg, the prescribed dose 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 nivolumab dose in mg, divided by 10 (the OPDIVO concentrate strength is 10 mg/mL).

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 (please see above).

Nivolumab in combination with ipilimumab in MPM:

The prescribed dose for the patient is 360 mg given regardless of body weight.

Nivolumab in combination with ipilimumab in OSCC:

The prescribed dose for the patient can be based on body weight (3 mg/kg) or 360 mg given regardless of body weight.

Nivolumab in combination with chemotherapy in resectable NSCLC:

The prescribed dose for the patient is 360 mg given regardless of body weight.

Nivolumab in combination with chemotherapy in OSCC:

The prescribed dose for the patient is 240 mg or 480 mg given regardless of body weight.

Nivolumab in combination with chemotherapy in gastric, GEJ or oesophageal adenocarcinoma:

The prescribed dose for the patient is 360 mg or 240 mg given regardless of body weight.

Nivolumab in combination with ipilimumab and chemotherapy:

The prescribed dose for the patient is 360 mg given regardless of body weight.

Nivolumab in combination with cabozantinib:

The prescribed dose for the patient is nivolumab 240 mg or 480 mg given regardless of body weight.

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.