OPDIVO Solution for injection Ref.[116349] Active ingredients:

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

Patients currently receiving intravenous nivolumab monotherapy, or in combination with chemotherapy or cabozantinib, may transition to OPDIVO solution for injection.

PD-L1 testing

If specified in the indication, patient selection for treatment with OPDIVO based on the tumour expression of PD-L1 should be assessed by a CE-marked in vitro IVD medical device test. If the CE-marked IVD is not available, an alternative validated test should be used (see sections 4.1, 4.4, and 5.1).

MSI/MMR testing

If specified in the indication, patient selection for treatment with OPDIVO based on MSI-H/dMMR tumour status should be assessed by a CE-marked IVD with the corresponding intended purpose. If the CE-marked IVD is not available, an alternative validated test should be used (see sections 4.1, 4.4, and 5.1).

Posology

OPDIVO as monotherapy

The recommended dose of OPDIVO solution for injection is either nivolumab 600 mg every 2 weeks or 1200 mg every 4 weeks (see section 5.1).

If patients need to be switched from the 600 mg every 2 weeks schedule to the 1200 mg every 4 weeks schedule, the first 1200 mg dose should be administered two weeks after the last 600 mg dose. Conversely, if patients need to be switched from the 1200 mg every 4 weeks schedule to the 600 mg every 2 weeks schedule, the first 600 mg dose should be administered four weeks after the last 1200 mg dose.

OPDIVO in combination with ipilimumab

Melanoma

Table 1. Recommended doses and infusion times for OPDIVO solution for infusion in combination with ipilimumab followed by OPDIVO solution for injection monotherapy for melanoma (see section 5.1):

Renal cell carcinoma (RCC)

Table 2. Recommended doses and infusion times for OPDIVO solution for infusion in combination with ipilimumab followed by OPDIVO solution for injection monotherapy for RCC:

dMMR or MSI-H colorectal cancer (CRC)

Table 3. Recommended doses and infusion times for OPDIVO solution for infusion in combination with ipilimumab followed by OPDIVO solution for injection monotherapy for dMMR or MSI-H CRC:

Hepatocellular carcinoma (HCC)

Table 4. Recommended doses and infusion times for OPDIVO solution for infusion in combination with ipilimumab followed by OPDIVO solution for injection monotherapy for the treatment of HCC (see sections 5.1 and 5.2):

^* Treatment is recommended until disease progression, unacceptable toxicity, or up to 24 months.

OPDIVO in combination with cabozantinib

Renal cell carcinoma (RCC)

Table 5. Recommended doses for OPDIVO solution for injection in combination with cabozantinib for the treatment of RCC:

^* 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.

OPDIVO in combination with chemotherapy

Oesophageal squamous cell carcinoma (OSCC)

Table 6. Recommended doses for administration of OPDIVO solution for injection in combination with fluoropyrimidine- and platinum-based chemotherapy for the treatment of OSCC (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 (GEJ) or oesophageal adenocarcinoma

Table 7. Recommended doses for administration of OPDIVO solution for injection in combination with fluoropyrimidine- and platinum-based chemotherapy for the treatment of gastric, GEJ or oesophageal adenocarcinoma (see section 5.1)*:

^* Treatment with nivolumab is recommended until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Urothelial carcinoma (UC)

Table 8. Recommended doses and infusion times for OPDIVO solution for infusion in combination with cisplatin and gemcitabine followed by OPDIVO solution for injection monotherapy for UC (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.

Neoadjuvant and adjuvant treatment of non-small cell lung cancer (NSCLC)

Table 9. Recommended doses and infusion times for OPDIVO solution for infusion in combination with platinum-based chemotherapy for neoadjuvant treatment followed by OPDIVO solution for injection monotherapy for adjuvant treatment of NSCLC:

^* Treatment is recommended until disease progression or recurrence, unacceptable toxicity, or up to 13 cycles (see section 5.1).

Duration of treatment

Treatment with OPDIVO, either as a monotherapy or in combination with 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.

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 10. 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 10. 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 experiencing immune-related myocarditis is not known.

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 card and be informed about the risks of OPDIVO (see also package leaflet).

When OPDIVO is administered intravenously 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 intravenous combination treatment or OPDIVO monotherapy administered intravenously or subcutaneously 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 10 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

Elderly

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

Renal impairment

Based on the population pharmacokinetic (PK) results for intravenous nivolumab, 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 for intravenous nivolumab, no dose adjustment is required in patients with mild or moderate hepatic impairment (see section 5.2). Data from patients with severe hepatic impairment are too limited to draw conclusions on this populations. OPDIVO must be administered with caution in patients with severe (total bilirubin >3 × ULN and any AST) hepatic impairment.

Paediatric population

The safety and efficacy of OPDIVO solution for injection in children below 18 years of age have not been established.

Method of administration

OPDIVO solution for injection is for subcutaneous use

It is important to check the vial labels to ensure that the appropriate formulation (intravenous or subcutaneous formulation) and dose is being administered to the patient as prescribed.

OPDIVO solution for injection is not intended for intravenous administration and must be given by subcutaneous injection only using the doses specified. More than one vial of OPDIVO solution for injection may be needed to give the total dose for the patient. For instructions on use and handling of the OPDIVO solution for injection before administration, see section 6.6.

Administer the full contents of the syringe of OPDIVO solution for injection into the subcutaneous tissue of the abdomen or thigh over a period of 3 to 5 minutes. The dose should not be split between two syringes or between two sites of administration. Alternate injection sites for successive injections. Do not inject into areas where the skin is tender, red, or bruised, or areas where there are scars or moles. If the administration of OPDIVO solution for injection is interrupted, it can be resumed at the same site, or at an alternate site.

During the treatment course with OPDIVO solution for injection, other medicinal products for subcutaneous administration should preferably be injected at different sites.

OPDIVO solution for infusion (intravenous formulation)

The Summary of Product Characteristics (SmPC) of OPDIVO concentrate for solution for infusion should be referred to for information on dosing instructions and method of administration.

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.

Storage in syringe:

From a microbiological point of view, once transferred from the vial to the syringe, the medicinal product should be used immediately since the medicinal product does not contain any antimicrobial preservative or bacteriostatic agents. If not used immediately, OPDIVO solution for injection transferred to the syringe can be stored in the refrigerator at 2°C to 8°C, protected from light for up to 7 days and/or at room temperature 20°C to 25°C and room light for up to 8 hours. Discard if storage time exceeds these limits. Aseptic handling should be ensured during the preparation of the syringe for injection.

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 preparation of the syringe, see section 6.3.

Type I glass vial with a butyl rubber stopper and an aluminium seal with a plastic orange flip-off cap containing 5 mL of solution for injection.

Pack of one vial.

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

Preparation of the syringe

OPDIVO solution for injection is for single use only and is ready to use.

OPDIVO solution for injection should NOT be diluted or mixed with other medicinal products.

OPDIVO solution for injection is compatible with polypropylene, polycarbonate, polyethylene, polyurethane, polyvinyl chloride, fluorinated ethylene propylene, and stainless steel.

OPDIVO solution for injection should be a clear to opalescent, colourless to yellow solution. Prior to use, visually inspect and discard if discoloured or contains extraneous particulate matter other than a few translucent-to-white particles.

Do not shake the vial.

A syringe and a transfer needle are needed to withdraw the medicinal product from the vial. OPDIVO solution for injection may be administered subcutaneously using a 23G-25G hypodermic injection needle or subcutaneous administration set (e.g., winged/butterfly).

If a dose of 600 mg is to be administered, allow 1 vial to reach room temperature, then withdraw 5 mL of OPDIVO solution for injection into the syringe.

If a dose of 1200 mg is to be administered, allow 2 vials to reach room temperature, then withdraw 10 mL of OPDIVO solution for injection into the syringe.

The hypodermic injection needle must be attached to the syringe immediately prior to administration to avoid clogging.

It is recommended to use the prepared dose immediately.

If storage is required (see section 6.3), apply a syringe tip cap prior to storage.

If stored in the refrigerator, allow the solution to reach ambient temperature before administration.

Disposal

Discard any unused solution remaining in the vial.

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