Consumer medicine information

Opdivo

Nivolumab

BRAND INFORMATION

Brand name

Opdivo

Active ingredient

Nivolumab

Schedule

SUMMARY CMI

OPDIVO^®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

WARNING: Important safety information is provided in a boxed warning in the full CMI. Read before using this medicine.

1. Why am I given OPDIVO?

OPDIVO contains the active ingredient nivolumab. OPDIVO is used to treat various kinds of cancer.

For more information, see Section 1. Why am I given OPDIVO? in the full CMI.

2. What should I know before I am given OPDIVO?

Do not use if you have ever had an allergic reaction to OPDIVO or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I am given OPDIVO? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with OPDIVO and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How am I given OPDIVO?

OPDIVO will be given to you in hospital or clinic under the supervision of an experienced doctor and/or nurse
It will be given to you as an infusion (a drip) into a vein (intravenously)
Your doctor will decide how many treatments you should be given

More instructions can be found in Section 4. How am I given OPDIVO? in the full CMI.

5. What should I know while receiving OPDIVO?

Things you should do	Tell any other doctors, dentists, nurses, and pharmacists who are treating you that you are being given OPDIVO Ensure you tell your doctor if you have autoimmune disease, any history of inflammation of the lungs, melanoma of the eye, if you have cancer that has spread to the brain, if you were previously given ipilimumab, another medicine for the treatment of advanced melanoma, and experienced side effects because of this medicine or if you are taking any medicines that suppress your immune system, such as corticosteroids OPDIVO acts on your immune system and may cause inflammation in parts of your body which may be life threatening and need treatment or withdrawal of OPDIVO Tell your doctor immediately if you have any signs or symptoms of possible side effects or if they get worse despite medical care or management
Things you should not do	Do not try to treat your symptoms with other medicines on your own without telling your doctor. Your doctor may give you other medicines to prevent complications or reduce your symptoms, your doctor may withhold the next dose of OPDIVO, or stop your treatment with OPDIVO altogether
Driving or using machines	OPDIVO is unlikely to affect your ability to drive or use machines; however, use caution when performing these activities and notify your doctor if you notice any changes to your ability

For more information, see Section 5. What should I know while receiving OPDIVO? in the full CMI.

6. Are there any side effects?

Like all medicines, OPDIVO can cause side effects. Your doctor will discuss potential side effects with you and will explain the risks and benefits of your treatment. Some side effects can be serious and you may require medical attention. Contact your doctor immediately or go to the Emergency Department at your nearest hospital if you have any signs or symptoms (changes to your normal self), particularly if they are getting worse or do not go away. For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

Both OPDIVO and ipilimumab act on your immune system and may cause inflammation in parts of your body. Inflammation may cause serious damage to your body and some inflammatory conditions may be life-threatening.

These side effects are most likely to begin during treatment, however, side effects can show up months after your last infusion.

IT IS IMPORTANT TO TELL YOUR DOCTOR IMMEDIATELY IF YOU HAVE, OR DEVELOP, ANY OF THE SYMPTOMS LISTED UNDER POSSIBLE SIDE EFFECTS.

FULL CMI

OPDIVO^® (op-DEE-voh)

Active ingredient: nivolumab (nee-vol-u-mab)

Consumer Medicine Information (CMI)

This leaflet provides important information about using OPDIVO. You should also speak to your doctor, nurse or pharmacist if you would like further information or if you have any concerns or questions about using OPDIVO.

Where to find information in this leaflet:

1. Why am I given OPDIVO?
2. What should I know before I am given OPDIVO?
3. What if I am taking other medicines?
4. How am I given OPDIVO?
5. What should I know while receiving OPDIVO?
6. Are there any side effects?
7. Product details

1. Why am I given OPDIVO?

OPDIVO contains the active ingredient nivolumab. OPDIVO is a protein which helps your immune system to attack and destroy cancer cells.

OPDIVO is used to treat:

Advanced skin cancer (unresectable or metastatic melanoma)
A type of lung cancer (advanced squamous and non-squamous non-small cell lung cancer)
A type of kidney cancer (clear cell renal cell carcinoma)
A type of head and neck cancer (squamous cell cancer of the head and neck)
A type of blood cancer called classical Hodgkin lymphoma
A type of bladder cancer (urothelial carcinoma)
A type of liver cancer (hepatocellular carcinoma)
A type of food pipe cancer (oesophageal squamous cell cancer), if your cancer has not responded, or if it has stopped responding, to earlier treatment
Cancer of the oesophagus (food pipe) or gastro-oesophageal junction (area which connects your food pipe and stomach) after chemoradiotherapy followed by surgical removal of the cancer
Bladder cancer (urothelial carcinoma) after surgical removal of the cancer. Treatment after surgery is also called adjuvant therapy.
Skin cancer (melanoma) after surgical removal of the cancer in adults and adolescents (12 years and older)

OPDIVO in combination with ipilimumab is used to treat:

Advanced melanoma (unresectable or metastatic melanoma)
A type of advanced kidney cancer (renal cell carcinoma)
A type of cancer that affects the lining of the lung (Malignant pleural mesothelioma)
A type of cancer of the food pipe (oesophageal squamous cell cancer).

OPDIVO in combination with ipilimumab and chemotherapy is used to treat:

A type of lung cancer (non-small cell lung cancer without certain biological markers)

OPDIVO in combination with cabozantinib is used to treat:

A type of kidney cancer (renal cell carcinoma)

OPDIVO in combination with chemotherapy is used to treat:

A type of cancer of the stomach (gastric adenocarcinoma), the connection between the stomach and food pipe (gastro-oesophageal junction adenocarcinoma) or the food pipe (oesophageal adenocarcinoma or oesophageal squamous cell cancer)
Lung cancer before you have surgery

2. What should I know before I am given OPDIVO?

Warnings

You should not be given OPDIVO if:

you are allergic to nivolumab, or any of the ingredients listed in Section 7. Product details

Always check the ingredients or talk to your doctor to make sure you can use this medicine.

Check with your doctor if you:

have an autoimmune disease (a condition where the body attacks its own cells) like Crohn's, ulcerative colitis or lupus
have any history of inflammation of the lungs
have been told your cancer has spread to your brain
have melanoma of the eye
were previously given ipilimumab, another medicine for the treatment of advanced melanoma, and experienced side effects because of this medicine.
are taking any medicines that suppress your immune system, such as corticosteroids, since these medicines may interfere with the effect of OPDIVO. However, once you are treated with OPDIVO, your doctor may give you corticosteroids to reduce any possible side effects that you may have during your treatment and this will not impact the effect of the medicine.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant, intend to become pregnant, or if you are breast-feeding.

You must not use OPDIVO if you are pregnant unless your doctor specifically recommends it.

The effects of OPDIVO in pregnant women are not known, but it is possible that the active substance, nivolumab, could harm an unborn baby.

You must use effective contraception while you are being treated with OPDIVO, and for at least 5 months following the last dose of OPDIVO, if you are a woman who could become pregnant
If you become pregnant while using OPDIVO, tell your doctor

You should stop breast-feeding if you are being treated with OPDIVO.

It is not known whether nivolumab gets into breast milk. A risk to the breast-fed infant cannot be excluded.

Use in children or adolescents

For treatment of adjuvant melanoma, it is recommended to use this medicine in adolescents (12 years and older).
For all other indications, it is not recommended to use this medicine in children or an adolescent (below 18 years) until further information becomes available.

Important information about some of the ingredients of OPDIVO

Tell your doctor if you are on a low-sodium (low-salt) diet before you are given OPDIVO. This medicine contains 2.5 mg sodium per mL of concentrate.

3. What if I am taking other medicines?

Tell your doctor, nurse or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription (over the counter) from your pharmacy, supermarket or health food shop.

Ask your doctor for advice before taking any medicine or dietary supplement/vitamin during your treatment.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect OPDIVO.

4. How am I given OPDIVO?

How is OPDIVO given

OPDIVO will be given to you in hospital or clinic under the supervision of an experienced doctor
It will be given to you as an infusion (a drip) into a vein (intravenously)
Your doctor will decide how many treatments you should be given

Dosage and frequency of administration of OPDIVO

The recommended dose (amount) and frequency (timing) of OPDIVO can be different depending on the type of cancer it is being used to treat
Some types of cancer are treated with OPDIVO in combination with other prescription anti-cancer medicines
Your doctor will advise you which treatments you will be given and will tell you about the dose and frequency of these treatments
Please refer to the Consumer Medicine Information of the other prescription anti-cancer medicines in order to understand the use of these other prescription anti-cancer medicines. If you have questions about these medicines, please ask your doctor

If you miss a dose of OPDIVO

It is very important for you to keep all appointments to receive OPDIVO. If you miss an appointment, ask your doctor when to schedule your next dose.

If you are given too much OPDIVO

As OPDIVO is given to you under the supervision of your doctor, it is unlikely that you will be given too much. However, if you experience any side effects after being given OPDIVO, tell your doctor immediately.

5. What should I know while receiving OPDIVO?

Things you should do

Tell any other doctors, dentists, nurses and pharmacists who are treating you that you are being given OPDIVO.

If you are about to be started on any new medicine, tell your doctor, dentist or pharmacist that you are being given OPDIVO.

Call your doctor straight away if you:

Have any signs or symptoms of possible side effects or if they get worse. See Section 6. Are there any side effects?
Develop symptoms of an allergic reaction. These symptoms 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.

Things you should not do

Do not try to treat your symptoms with other medicines on your own without telling your doctor.

Your doctor may:

Give you other medicines in order to prevent complications and reduce your symptoms
Withhold the next dose of OPDIVO
Or stop your treatment with OPDIVO altogether

Please note that these signs and symptoms are sometimes delayed, and may develop weeks or months after your last dose. Before treatment, your doctor will check your general health. You will also have blood tests during treatment.

Take special care with OPDIVO

OPDIVO is a medicine that influences your immune system and may cause inflammation in parts of your body. Inflammation may cause serious damage to your body and some inflammatory conditions may be life threatening and need treatment or withdrawal of OPDIVO
Tell your doctor immediately if you have any of the symptoms of inflammation listed in Section 6. Are there any side effects?

Driving or using machines

No studies on the effects of OPDIVO on the ability to drive and use machines have been performed.

OPDIVO is unlikely to affect your ability to drive or use machines; however, use caution when performing these activities until you are sure that OPDIVO does not adversely affect you and notify your doctor if you notice any changes to your ability.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Serious side effects

Serious side effects

What to do

Lung problems:

Problems with your lungs such as breathing difficulties, shortness of breath, or cough. These may be signs of inflammation of the lungs (pneumonitis or interstitial lung disease)

Stomach and Intestinal problems:

Inflammation of the intestines (colitis), stomach (gastritis) and duodenum (duodenitis) which can worsen to bleeding or bowel perforation
Symptoms may include diarrhoea (watery, loose or soft stools), an increased number of bowel movements (an increase by two or more per day), constipation, vomiting, nausea, mucus and blood in your stools, or darker-coloured stools, stomach pain or tenderness in your stomach area

Liver problems:

Inflammation of the liver (hepatitis) and Inflammation of the bile duct system (cholangitis).
Symptoms may include yellowing of the eyes or skin (jaundice), pain on the right side of your stomach area, tiredness, nausea or vomiting, fever or chills

Kidney problems:

Inflammation in the kidney (nephritis)
Signs and symptoms may include abnormal kidney function tests, decreased volume of urine and kidney failure (including abrupt loss of kidney function)

Hormone gland problems:

Underactive thyroid gland, which can cause tiredness or weight gain
Overactive thyroid gland, which can cause rapid heart rate, sweating and weight loss
Decreased secretion of hormones produced by adrenal glands (glands situated above the kidneys), underactive function (hypopituitarism) or inflammation (hypophysitis) of the pituitary gland situated at the base of the brain, swelling of the thyroid gland
Decrease in parathyroid hormone
Acid in the blood produced by diabetes (diabetic ketoacidosis)
Excessive thirst, the passing of a greatly increased amount of urine, increase in appetite with a loss of weight, feeling tired, drowsy, weak, depressed, irritable and generally unwell (diabetes)

Skin problems:

Inflammation of the skin that can lead to rash and itching
Severe and possibly fatal peeling of the skin (toxic epidermal necrolysis, Steven-Johnson syndrome)
Severe condition of the skin that causes red, often itchy spots, similar to rash of measles, which starts on the limbs and sometimes on the face and the rest of the body (erythema multiforme), skin disease with thickened patches of red skin, often silvery scales (psoriasis), hives (itchy, bumpy rash)

Brain and nervous system problems:

Damage to nerves causing numbness and weakness (polyneuropathy)
Inflammation of the brain (encephalitis)
A condition in which the muscles become weak and tire easily (myasthenic syndrome)
Inflammation of the nerves causing numbness, weakness, tingling or burning pain of the arms and legs, headaches, dizziness (autoimmune neuropathy)
Loss of the covering around the nerves (demyelination) pain
A temporary inflammation of the nerves that causes pain, weakness and paralysis in the extremities (Guillain-Barré syndrome)
Sensations like numbness and tingling (paraesthesia), dizziness
Inflammation of the spinal cord (myelitis) causing back and neck pain, weakness in the arms or legs, loss of bladder or bowel control

Complications of allogeneic Haematopoietic Stem Cell Transplant (HSCT):

Complications of stem cell transplant that uses donor cells (allogeneic) may occur after treatment with OPDIVO.
These complications can be severe and can lead to death. Your healthcare provider will monitor you for signs of complications if you have an allogeneic stem cell transplant.

Problems in other organs:

Inflammation of the heart (myocarditis). Symptoms may include shortness of breath, fatigue, palpitations or chest pain
Changes in the rhythm or rate of the heart, abnormal heart rhythm
Inflammation of muscles (myositis). Symptoms may include muscle pain, stiffness, weakness, chest pain or severe fatigue
Muscle breakdown/injury (rhabdomyolysis). Symptoms may include muscle pain, weakness, nausea or vomiting.
Inflammation of the eye, which causes pain and redness, blurred vision
Solid organ transplant rejection
A condition where the immune system mistakenly destroys red blood cells (oxygen carrying cells) and results in decreased number of red blood cells (autoimmune haemolytic anaemia)
Inflammation throughout the body (systemic inflammatory response syndrome) leading to redness and swelling (oedema) in the affected parts, intense pain, fatigue, fast heart rate, abnormal breathing, fever or chills

Infusion reactions:

Allergic reaction, reaction related to the infusion of the medicine
Life threatening allergic reaction

Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Other side effects

Other side effects	What to do
The following side effects have been reported in clinical trials when OPDIVO has been given alone: Very Common side effects Diarrhoea (watery, loose or soft stools), nausea Skin rash sometimes with blisters, itching Feeling tired or weak Common side effects Infections of the upper respiratory tract Decreased appetite Coughing, shortness of breath (dyspnoea) Stomach pain, constipation Mouth ulcers and cold sores (stomatitis), vomiting, dry mouth Skin colour changes in patches (vitiligo), dry skin, redness of the skin, hair loss or thinning Pain in the muscles, bones and joints Fever, oedema (swelling) High blood pressure (hypertension) dry eye	Speak to your doctor if you have any of these side effects and they worry you.
The following side effects have been reported in clinical trials when OPDIVO has been given in combination with ipilimumab: Very Common side effects Decreased appetite Headache Shortness of breath (dyspnoea) Skin rash sometimes with blisters, itching Pain in the joints, muscles and bones Feeling tired or weak Fever Common side effects Serious lung infection (pneumonia), infections of the upper respiratory tract Dehydration Inflammation of the eye, which causes pain and redness, blurred vision Fast heart rate High blood pressure (hypertension) Mouth ulcers and cold sores (stomatitis), inflammation of the pancreas (pancreatitis), constipation, dry mouth Skin colour change in patches (vitiligo), dry skin, redness of the skin, unusual hair loss or thinning, hives (itchy rash) Pain in the muscles and bones Inflammation of the joints (arthritis) Oedema (swelling), pain	Speak to your doctor if you have any of these side effects and they worry you.
The following side effects have been reported in clinical trials when OPDIVO has been given in combination with ipilimumab and chemotherapy Very Common side effects Decreased appetite Diarrhoea (watery, loose or soft stools), vomiting, nausea Skin rash sometimes with blisters, itching Feeling tired or weak Common side effects Conjunctivitis Serious lung infection (pneumonia), infections of the upper respiratory tract Dry eyes headache Shortness of breath (dyspnoea) Mouth ulcers and cold sores (stomatitis), inflammation of the pancreas (pancreatitis), constipation, dry mouth Dry skin, redness of the skin, unusual hair loss or thinning Pain in the joints, muscles and bones, inflammation of the joints Fever Oedema (swelling)	Speak to your doctor if you have any of these side effects and they worry you.
The following side effects have been reported in clinical trials when OPDIVO has been given in combination with cabozantinib Very Common side effects Decreased appetite, altered sense of taste High blood pressure (hypertension) Hoarseness Diarrhoea, nausea, mouth ulcers and cold sores (stomatitism), vomiting, abdominal pain, indigestion Blisters, pain of the hands or soles of the feet, rash or redness of the skin, rash, itching Feeling tired or weak Common side effects Infections of the upper respiratory tract Dehydration Headache, dizziness, inflammation of the nerves causing numbness or burning pain of the arms and legs Dry eye Blood clots Dry mouth, constipation, inflammation of the stomach (gastritis), oral pain Dry skin, unusual hair loss or thinning, redness of the skin, hair colour change Pain in the joints, muscle spasm, pain in the muscles or bones, pains, inflammation in the joints Oedema (swelling), fever, pain	Speak to your doctor if you have any of these side effects and they worry you.
The following side effects have been reported in clinical trials when OPDIVO has been given in combination with chemotherapy Very Common side effects Decreased appetite Constipation Diarrhoea (watery, loose or soft stools), vomiting, nausea Mouth ulcers and cold sores (stomatitis) Feeling tired or weak Skin rash sometimes with blisters, itching, tingling and tenderness developing to symmetrical redness, swelling and pain primarily on the palm of the hand and sole of the foot (palmar-plantar erythrodysaesthaesia syndrome) Constipation Common side effects Serious lung infection (pneumonia) Headache Dry eyes Blurred vision Shortness of breath (dyspnoea) Blood clots, low blood pressure (hypotension) Dry mouth Abdominal pain Dry skin, redness of the skin, unusual hair loss or thinning, skin colour change in patches, hives (itchy rash) Pain in the joints, muscles and bones, inflammation of the joints, muscle weakness Fever Oedema (swelling)	Speak to your doctor if you have any of these side effects and they worry you.

Tell your doctor, nurse or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

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

What OPDIVO contains

Active ingredient (main ingredient)	nivolumab
Other ingredients (inactive ingredients)	sodium citrate dihydrate sodium chloride mannitol (E421) pentetic acid polysorbate 80 sodium hydroxide hydrochloric acid water for injections

Do not take this medicine if you are allergic to any of these ingredients.

What OPDIVO looks like

OPDIVO concentrate for solution for infusion is a clear to opalescent, colourless to pale yellow liquid that may contain light (few) particles.

OPDIVO is available in the following presentations:

OPDIVO (nivolumab) concentrate solution for infusion 40mg in 4mL (10mg/mL) AUST R 231867
OPDIVO (nivolumab) concentrate solution for infusion 100mg in 10mL (10mg/mL) AUST R 231868
OPDIVO (nivolumab) concentrate solution for infusion 240mg in 24mL (10mg/mL) AUST R 318057 (not marketed)

Who distributes OPDIVO

Bristol-Myers Squibb Australia Pty Ltd
Level 2, 4 Nexus Court
Mulgrave VIC 3170 Australia.
Toll free number: 1800 067 567
Email: [email protected]

OPDIVO^® (nivolumab) is a registered trademark of Bristol-Myers Squibb Company

This leaflet was prepared in January 2024.

Published by MIMS February 2024

BRAND INFORMATION

Brand name

Opdivo

Active ingredient

Nivolumab

Schedule

1 Name of Medicine

Nivolumab.

2 Qualitative and Quantitative Composition

10 mg/mL concentrate solution for infusion.
Each 1 mL of concentrate contains 10 mg of nivolumab.
One 10 mL vial contains 40 mg of nivolumab in 4 mL.
One 10 mL vial contains 100 mg of nivolumab in 10 mL.
One 25 mL vial contains 240 mg of nivolumab in 24 mL.
Opdivo (nivolumab (rch)) is a fully human anti-PD-1 monoclonal antibody (IgG4) produced in mammalian (Chinese hamster ovary) cells by recombinant DNA technology.

Excipient with known effect.

Each 1 mL of concentrate contains 0.1 mmol (or 2.5 mg) sodium.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Concentrate for solution for infusion.
Clear to opalescent, colourless to pale yellow liquid that may contain few light particles. The solution has a pH of approximately 6.0 and an osmolarity of approximately 340 mOsm/kg.

4 Clinical Particulars

4.1 Therapeutic Indications

Melanoma.

Opdivo, as monotherapy, is indicated for the adjuvant treatment of adults and adolescent patients 12 years and older with completely resected Stage IIB, IIC, III or IV melanoma.
Opdivo, as monotherapy, is indicated for the treatment of patients with unresectable or metastatic melanoma.
Opdivo, in combination with ipilimumab, is indicated for the treatment of patients with unresectable or metastatic melanoma. The approval of this indication is based on a pre-specified comparison to ipilimumab monotherapy. All analyses comparing nivolumab monotherapy with the nivolumab/ipilimumab combination are descriptive.

Non-small cell lung cancer (NSCLC).

Opdivo, in combination with platinum-doublet chemotherapy, is indicated for the neoadjuvant treatment of patients with resectable non-small cell lung cancer (NSCLC).
Opdivo, in combination with ipilimumab and 2 cycles of platinum-doublet chemotherapy, is indicated for the first-line treatment of patients with metastatic or recurrent non-small cell lung cancer (NSCLC) with no EGFR or ALK genomic tumour aberrations.
Opdivo, as monotherapy, is indicated for the treatment of locally advanced or metastatic squamous non-small cell lung cancer (NSCLC) with progression on or after prior chemotherapy.
Opdivo, as monotherapy, is indicated for the treatment of locally advanced or metastatic non squamous non-small cell lung cancer (NSCLC) with progression on or after prior chemotherapy. In patients with tumour EGFR or ALK genomic aberrations, Opdivo should be used after progression on or after targeted therapy.

Malignant pleural mesothelioma (MPM).

Opdivo, in combination with ipilimumab, is indicated for the first-line treatment of patients with unresectable malignant pleural mesothelioma.

Renal cell carcinoma (RCC).

Opdivo, in combination with ipilimumab, is indicated for the treatment of patients with intermediate/poor-risk, previously untreated advanced renal cell carcinoma.
Opdivo, in combination with cabozantinib, is indicated for the first-line treatment of patients with advanced renal cell carcinoma.
Opdivo, as monotherapy, is indicated for the treatment of patients with advanced clear cell renal cell carcinoma after prior anti-angiogenic therapy.

Classical Hodgkin lymphoma (cHL).

Opdivo, as monotherapy, is indicated for the treatment of patients with relapsed or refractory classical Hodgkin lymphoma (cHL) after autologous stem cell transplant and treatment with brentuximab vedotin. The approval of this indication is based on objective response rate in a single arm study.

Squamous cell carcinoma of the head and neck (SCCHN).

Opdivo, as monotherapy, is indicated for the treatment of recurrent or metastatic squamous cell cancer of the head and neck in patients progressing on or after platinum based therapy.

Urothelial carcinoma (UC).

Opdivo, as monotherapy, is indicated for the adjuvant treatment of patients with muscle invasive urothelial carcinoma (MIUC) who are at high risk of recurrence after undergoing radical resection of MIUC.
Opdivo, as monotherapy, is indicated for the treatment of patients with locally advanced unresectable or metastatic urothelial carcinoma after prior platinum-containing therapy. The approval of this indication is based on objective response rate and duration of response in a single arm study.

Hepatocellular carcinoma (HCC).

Opdivo, as monotherapy, is indicated for the treatment of patients with hepatocellular carcinoma after prior sorafenib therapy. This indication is approved based on objective response rate and duration of response in a single arm study. An improvement in survival or disease-related symptoms has not been established.

Oesophageal squamous cell carcinoma (OSCC).

Opdivo in combination with ipilimumab is indicated for the first-line treatment of patients with unresectable advanced, recurrent or metastatic oesophageal squamous cell carcinoma with tumour cell PD-L1 expression ≥ 1% as determined by a validated test.
Opdivo in combination with fluoropyrimidine- and platinum-based combination chemotherapy is indicated for the first-line treatment of patients with unresectable advanced, recurrent or metastatic oesophageal squamous cell carcinoma with tumour cell PD-L1 expression ≥ 1% as determined by a validated test.
Opdivo, as monotherapy, is indicated for the treatment of patients with unresectable advanced, recurrent or metastatic oesophageal squamous cell carcinoma after prior fluoropyrimidine and platinum based chemotherapy.

Adjuvant oesophageal cancer (OC) or gastro-oesophageal junction cancer (GOJC).

Opdivo, as monotherapy, is indicated for the adjuvant treatment of resected oesophageal or gastro-oesophageal junction cancer in patients who have received neoadjuvant chemoradiotherapy.

Gastric cancer (GC), gastro-oesophageal junction cancer (GOJC), or oesophageal adenocarcinoma (OAC).

Opdivo, in combination with fluoropyrimidine- and platinum-based combination chemotherapy, is indicated for the first-line treatment of patients with HER2 negative advanced or metastatic gastric or gastro-oesophageal junction or oesophageal adenocarcinoma.

4.2 Dose and Method of Administration

Treatment must be initiated and supervised by specialist physicians experienced in the treatment of cancer.
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 Section 4.1; Section 4.4; Section 5.1).
Opdivo infusion must not be administered as an intravenous push or bolus injection.
Dose escalation or reduction is not recommended. Guidelines for permanent discontinuation or withholding of doses are described in Table 3. Detailed guidelines for the management of immune-related adverse reactions are described in Section 4.4 Special Warnings and Precautions for Use.
Nivolumab was originally developed using an every-two-weeks monotherapy dosing regimen (see Section 5.1 Pharmacodynamic Properties, Clinical trials). Subsequent approval of the every-four-weeks monotherapy dosing regimen was based on pharmacokinetic and exposure-response modelling and simulations, with supporting clinical safety data. Data from randomised controlled trials of every-two-weeks versus every-four-weeks dosing of nivolumab, with sufficient sample size to demonstrate non-inferiority using clinical endpoint data (such as PFS or OS), is not available.

Recommended doses.

The recommended doses of Opdivo as a single agent are presented in Table 1.

The recommended doses of Opdivo in combination with other therapeutic agents are presented in Table 2. See respective Product Information for each therapeutic agent administered in combination with Opdivo for the recommended dose information, as appropriate.

Recommended treatment modifications for Opdivo as monotherapy and Opdivo in combination with other therapeutic agents.

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. When nivolumab is administered in combination, see Product Information of the other combination therapy agents regarding dosing.
When Opdivo is administered in combination with ipilimumab, if either agent is withheld, the other agent should also be withheld. 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 for clinically stable patients with initial evidence of disease progression until disease progression is confirmed.
When Opdivo is administered in combination with chemotherapy, refer to the Product Information of the other combination therapy agents regarding dosing. Dose escalation or reduction is not recommended for Opdivo. 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.

For RCC patients treated with Opdivo in combination with cabozantinib, see the Product Information regarding treatment modifications of cabozantinib.
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 Product Information.
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 patients.

The safety and effectiveness of Opdivo have been established in paediatric patients aged 12 years and older as a single agent for the adjuvant treatment of completely resected Stage IIB, Stage IIC, Stage III, or Stage IV melanoma.

Elderly patients.

No overall differences in safety or efficacy were reported between elderly (≥ 65 years) and younger patients (< 65 years). No dose adjustment is required for elderly patients (≥ 65 years) (see Section 5.2 Pharmacokinetic Properties).

Patients with 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 Pharmacokinetic Properties). Opdivo has not been studied in patients with severe renal impairment.

Patients with hepatic impairment.

Based on the population PK results, no dose adjustment is required in patients with mild or moderate hepatic impairment, although data in moderate hepatic impairment are limited (see Section 5.2 Pharmacokinetic Properties). Opdivo has not been studied in patients with severe hepatic impairment or cirrhosis of Child-Pugh B or C severity and Opdivo must be administered with caution in these patients (see Section 4.4 Special Warnings and Precautions for Use).

Method of administration.

Opdivo infusion must not be administered as an intravenous push or bolus injection.
Administer the Opdivo infusion intravenously over a period of 30 minutes.
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.
Administer Opdivo or Opdivo in combination with other therapeutic agents as follows:
With ipilimumab: administer Opdivo first followed by ipilimumab on the same day.
With platinum-doublet chemotherapy: administer Opdivo first followed by platinum doublet chemotherapy on the same day.
With ipilimumab and platinum-doublet chemotherapy: administer Opdivo first followed by ipilimumab and then platinum-doublet chemotherapy on the same day.
With fluoropyrimidine- and platinum-containing chemotherapy: administer Opdivo first followed by fluoropyrimidine- and platinum-containing chemotherapy on the same day.
Use separate infusion bags and filters for each infusion. Administer Opdivo first followed by ipilimumab, no earlier than 30 minutes after completion of the Opdivo infusion.
Use an infusion set and an in-line, sterile, non-pyrogenic, low protein binding filter (pore size of 0.2 micrometer to 1.2 micrometer).
Opdivo infusion is compatible with: PVC or non-PVC containers, polyolefin containers, glass bottles, PVC infusion sets, in-line filters with polyethersulfone membranes with pore sizes of 0.2 micrometer to 1.2 micrometer.
After administration of dose, flush the line with sodium chloride 9 mg/mL (0.9%) solution for injection or 50 mg/mL (5%) glucose solution for injection.
Calculating the dose. More than one vial of Opdivo concentrate may be needed to give the total dose for the patient.
When the prescribed dose for the patient is 240 mg, 360 mg or 480 mg, it is given regardless of body weight.
When the prescribed dose for the patient is 3 mg/kg or 1 mg/kg, calculate the total dose to be given.
Each 4 mL vial of Opdivo concentrate contains 40 mg of nivolumab; each 10 mL vial of Opdivo contains 100 mg of nivolumab.
The total nivolumab dose in mg = the patient's weight in kg x 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. Preparation should be performed by trained personnel in accordance with good practices rules, especially with respect to asepsis.
Opdivo can be used for intravenous administration without dilution, after transfer to an infusion container using an appropriate sterile syringe.
Opdivo can also be used for intravenous administration after diluting with either sodium chloride 9 mg/mL (0.9%) solution for injection or 50 mg/mL (5%) glucose solution for injection. For 3 mg/kg or 1 mg/kg dose, the final infusion concentration should range between 1 and 10 mg/mL. For 240 mg, 360 mg or 480 mg, the concentrate may be diluted to not exceed a total infusion volume of 160 mL. For patients with body weight less than 40 kg, the total volume of infusion must not exceed 4 mL/kg of body weight.

Step 1.

Inspect the Opdivo concentrate for particulate matter or discoloration. Do not shake. Opdivo concentrate is a clear to opalescent, colourless to pale yellow liquid that may contain a few light particles. 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 IV container (PVC, non-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.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in Section 6.1.

4.4 Special Warnings and Precautions for Use

When assessing the PD-L1 status of the tumour, it is important that a validated test is used.
Early identification of adverse reactions and appropriate intervention are an important part of the safe use of Opdivo with or without ipilimumab.
Opdivo monotherapy is associated with immune related adverse reactions. In clinical trials, almost all immune-related adverse reactions have occurred at higher frequencies when Opdivo was administered in combination with ipilimumab compared with Opdivo as a monotherapy. Most immune-related adverse reactions improved or resolved with appropriate management, including initiation of corticosteroids and dose modifications.
Patients should be monitored continuously, as an immune-related adverse reaction with Opdivo monotherapy or Opdivo in combination with ipilimumab may occur at any time during or after discontinuation of therapy. The majority of these initially manifested during treatment; however, a minority occurred weeks to months after discontinuation.
Clinicians should consider immune-related adverse reactions for all unexplained illnesses. Adequate evaluation should be performed to confirm aetiology or exclude other causes.
Based on the severity of the adverse reaction, Opdivo monotherapy or Opdivo in combination with ipilimumab should be withheld (see Section 4.2 Dose and Method of Administration) and corticosteroids administered.
If immunosuppression with corticosteroids is used to treat an adverse reaction, a taper of at least one month duration should be initiated upon improvement. Rapid tapering may lead to worsening or recurrence of the adverse reaction.
Non-corticosteroid immunosuppressive therapy should be added if there is worsening or no improvement despite corticosteroid use.
Opdivo monotherapy or Opdivo in combination with ipilimumab should not be resumed while the patient is receiving immunosuppressive doses of corticosteroids or other immunosuppressive therapy.
Prophylactic antibiotics should be used to prevent opportunistic infections in patients receiving immunosuppressive therapy.
Opdivo monotherapy or Opdivo in combination with ipilimumab must be permanently discontinued for any severe immune related adverse reaction that recurs and for any life threatening immune related adverse reaction (see Section 4.2 Dose and Method of Administration).

Immune-related pneumonitis.

Severe pneumonitis or interstitial lung disease, including fatal cases, has been observed with Opdivo monotherapy, Opdivo in combination with ipilimumab or Opdivo in combination with chemotherapy.
Patients should be monitored for signs and symptoms of pneumonitis such as radiographic changes (e.g. focal ground glass opacities, patchy filtrates), dyspnoea, and hypoxia. Infectious and disease-related aetiologies should be ruled out.
For Grade 3 or 4 pneumonitis, Opdivo monotherapy or Opdivo in combination with ipilimumab, must be permanently discontinued and corticosteroids should be initiated at a dose of 2 to 4 mg/kg/day methylprednisolone equivalents.
For Grade 2 (symptomatic) pneumonitis, Opdivo monotherapy or Opdivo in combination with ipilimumab, should be withheld and corticosteroids initiated at a dose of 1 mg/kg/day methylprednisolone equivalents. Upon improvement, Opdivo monotherapy or Opdivo in combination with ipilimumab may be resumed (after corticosteroid taper). If worsening or no improvement occurs despite initiation of corticosteroids, corticosteroid dose should be increased to 2 to 4 mg/kg/day methylprednisolone equivalents and Opdivo monotherapy or Opdivo in combination with ipilimumab must be permanently discontinued.

Immune-related colitis.

Severe diarrhoea or colitis has been observed with Opdivo monotherapy or Opdivo in combination with ipilimumab. Patients should be monitored for diarrhoea and additional symptoms of colitis, such as abdominal pain and mucus or blood in stool. Infectious and disease-related aetiologies should be ruled out. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid refractory immune-related colitis. Stool infections work-up (including CMV, other viral aetiology, culture, Clostridium difficile, ova, and parasite) should be performed upon presentation of diarrhoea or colitis to exclude infectious or other alternate aetiologies.
For Grade 4 diarrhoea or colitis, Opdivo monotherapy or Opdivo in combination with ipilimumab, must be permanently discontinued and corticosteroids should be initiated at a dose of 1 to 2 mg/kg/day methylprednisolone equivalents.
For Grade 3 diarrhoea or colitis observed with Opdivo in combination with ipilimumab, permanently discontinue both agents and follow the management guideline for Grade 4 diarrhoea or colitis above.
Opdivo monotherapy should be withheld for Grade 3 diarrhoea or colitis and corticosteroids initiated at a dose of 1 to 2 mg/kg/day methylprednisolone equivalents. Upon improvement, Opdivo monotherapy may be resumed (after corticosteroid taper). If worsening or no improvement occurs despite initiation of corticosteroids, Opdivo monotherapy must be permanently discontinued.
For Grade 2 diarrhoea or colitis, Opdivo monotherapy or Opdivo in combination with ipilimumab, should be withheld. Persistent diarrhoea or colitis should be managed with corticosteroids at a dose of 0.5 to 1 mg/kg/day methylprednisolone equivalents. Upon improvement, Opdivo monotherapy or Opdivo in combination with ipilimumab, may be resumed (after corticosteroid taper). If worsening or no improvement occurs despite initiation of corticosteroids, corticosteroid dose should be increased to 1 to 2 mg/kg/day methylprednisolone equivalents and Opdivo monotherapy or Opdivo in combination with ipilimumab, must be permanently discontinued.
The experience from clinical trials on the management of corticosteroid refractory diarrhoea or colitis is limited. Addition of an alternative immunosuppressive agent to the corticosteroid therapy, or replacement of the corticosteroid therapy, should be considered in corticosteroid-refractory immune-related colitis if other causes are excluded (including CMV infection/reactivation evaluated with viral PCR on biopsy, and other viral, bacterial, and parasitic aetiology).

Immune-related hepatitis.

Severe hepatitis has been observed with Opdivo monotherapy or Opdivo in combination with ipilimumab. Infectious and disease-related aetiologies should be ruled out.
Elevations in liver function tests may develop in the absence of clinical symptoms. Monitor patients for abnormal liver tests prior to and periodically during treatment as indicated based on clinical evaluation.
For Grade 3 or 4 transaminase or total bilirubin elevation, Opdivo monotherapy or Opdivo in combination with ipilimumab, must be permanently discontinued and corticosteroids should be initiated at a dose of 1 to 2 mg/kg/day methylprednisolone equivalents.
For Grade 2 transaminase or total bilirubin elevation, Opdivo monotherapy or Opdivo in combination with ipilimumab should be withheld. Persistent elevations in these laboratory values should be managed with corticosteroids at a dose of 0.5 to 1 mg/kg/day methylprednisolone equivalents. Upon improvement, Opdivo monotherapy or Opdivo in combination with ipilimumab may be resumed (after corticosteroid taper).
If worsening or no improvement occurs despite initiation of corticosteroids, corticosteroid dose should be increased to 1 to 2 mg/kg/day methylprednisolone equivalents and Opdivo monotherapy or Opdivo in combination with ipilimumab must be permanently discontinued.

Management of transaminase elevation in patients with HCC (also see Section 4.2 Dose and Method of Administration).

In patients with HCC, nivolumab monotherapy should be withheld or permanently discontinued based on the following criteria and corticosteroids initiated at a dose of 1 to 2 mg/kg methylprednisolone equivalent.
For Grade 1 transaminase levels at baseline (> 1 to 3 times ULN) and on-treatment transaminase elevation at > 5 to 10 times ULN, nivolumab should be withheld.
For Grade 2 transaminase levels at baseline (> 3 to 5 times ULN) and on-treatment transaminase elevation at > 8 to 10 times ULN, nivolumab should be withheld.
Regardless of baseline transaminase levels, nivolumab must be permanently discontinued for on-treatment transaminase increases > 10 times ULN or Grade 3 or 4 total bilirubin increases.

Immune-related nephritis and renal dysfunction.

Severe nephritis and renal dysfunction have been observed with Opdivo monotherapy or Opdivo in combination with ipilimumab. Disease-related aetiologies should be ruled out.
Creatinine elevations may develop in the absence of clinical symptoms. Monitor patients for elevated serum creatinine prior to and periodically during treatment as indicated based on clinical evaluation.
For Grade 4 serum creatinine elevation, Opdivo monotherapy or Opdivo in combination with ipilimumab must be permanently discontinued and corticosteroids should be initiated at a dose of 1 to 2 mg/kg/day methylprednisolone equivalents.
For Grade 2 or 3 serum creatinine elevation, Opdivo monotherapy or Opdivo in combination with ipilimumab should be withheld and corticosteroids should be initiated at a dose of 0.5 to 1 mg/kg/day methylprednisolone equivalents. Upon improvement, Opdivo monotherapy or Opdivo in combination with ipilimumab, may be resumed (after corticosteroid taper). If worsening or no improvement occurs despite initiation of corticosteroids, corticosteroid dose should be increased to 1 to 2 mg/kg/day methylprednisolone equivalents and Opdivo monotherapy or Opdivo in combination with ipilimumab, must be permanently discontinued.

Immune-related endocrinopathies.

Severe endocrinopathies, including hypothyroidism, hyperthyroidism, adrenal insufficiency (including secondary adrenocortical insufficiency), hypophysitis (including hypopituitarism), hypoparathyroidism, diabetes mellitus, and diabetic ketoacidosis have been observed with Opdivo monotherapy or Opdivo in combination with ipilimumab.
Patients should be monitored for clinical signs and symptoms of endocrinopathies and for changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation).
Patients may present with fatigue, headache, mental status changes, abdominal pain, unusual bowel habits, hypotension, or other nonspecific symptoms which may resemble those associated with other causes such as brain metastasis or underlying disease. Unless an alternate aetiology has been identified, signs or symptoms of endocrinopathies should be considered immune-related.
For symptomatic hypothyroidism, Opdivo monotherapy or Opdivo in combination with ipilimumab, should be withheld, and thyroid hormone replacement should be initiated as needed. For symptomatic hyperthyroidism, Opdivo monotherapy or Opdivo in combination with ipilimumab, should be withheld and an antithyroid medicine should be initiated as needed. Corticosteroids at a dose of 1 to 2 mg/kg/day methylprednisolone equivalents should also be considered if acute inflammation of the thyroid is suspected. Upon improvement, Opdivo monotherapy or Opdivo in combination with ipilimumab, may be resumed (after corticosteroid taper). Monitoring of thyroid function should continue to ensure appropriate hormone replacement is utilised. Opdivo monotherapy or Opdivo in combination with ipilimumab should be permanently discontinued for life-threatening (Grade 4) hypothyroidism or hyperthyroidism.
For symptomatic Grade 2 adrenal insufficiency, Opdivo monotherapy or Opdivo in combination with ipilimumab, should be withheld, and physiologic corticosteroid replacement should be initiated as needed. Opdivo monotherapy or Opdivo in combination with ipilimumab must be permanently discontinued for severe (Grade 3) or life-threatening (Grade 4) adrenal insufficiency. Monitoring of adrenal function and hormone levels should continue to ensure appropriate corticosteroid replacement is utilised.
For symptomatic Grade 2 or 3 hypophysitis, Opdivo monotherapy or Opdivo in combination with ipilimumab should be withheld, and hormone replacement should be initiated as needed. Corticosteroids at a dose of 1 to 2 mg/kg/day methylprednisolone equivalents should also be considered if acute inflammation of the pituitary gland is suspected. Upon improvement, Opdivo monotherapy or Opdivo in combination with ipilimumab may be resumed (after corticosteroid taper). Opdivo monotherapy or Opdivo in combination with ipilimumab must be permanently discontinued for life-threatening (Grade 4) hypophysitis. Monitoring of pituitary function and hormone levels should continue to ensure appropriate hormone replacement is utilised.
For symptomatic diabetes, Opdivo monotherapy or Opdivo in combination with ipilimumab should be withheld, and insulin replacement should be initiated as needed. Monitoring of blood sugar should continue to ensure appropriate insulin replacement is utilised. Opdivo monotherapy or Opdivo in combination with ipilimumab should be permanently discontinued for life-threatening (Grade 4) diabetes.

Immune-related skin adverse reactions.

Patients should be monitored for rash. Severe rash has been observed with Opdivo in combination with ipilimumab and less commonly with Opdivo monotherapy. Opdivo monotherapy or Opdivo in combination with ipilimumab should be withheld for Grade 3 rash and permanently discontinued for Grade 4 rash. Severe rash should be managed with high-dose corticosteroids at a dose of 1 to 2 mg/kg/day methylprednisolone equivalents.
Rare cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), some with fatal outcome, have been observed. If symptoms or signs of SJS or TEN appear, Opdivo or Opdivo in combination with ipilimumab should be withheld and the patient referred for specialist assessment and treatment. If the patient has confirmed SJS or TEN, permanent discontinuation of Opdivo or Opdivo in combination with ipilimumab is recommended.
Caution should be used when considering the use of Opdivo in a patient who has previously experienced a severe or life-threatening skin adverse reaction on prior treatment with other immunostimulatory anticancer agents.

Immune-related neurological adverse reactions.

The following adverse events have been observed across clinical trials of Opdivo or Opdivo in combination with ipilimumab: demyelination, autoimmune neuropathy (including facial and abducens nerve paresis), Guillain-Barré syndrome, myasthenic syndrome/myasthenia gravis, and encephalitis.
Withhold Opdivo in patients with new-onset moderate to severe neurologic signs or symptoms and evaluate to rule out infectious or other causes of moderate to severe neurologic deterioration. Evaluation may include, consultation with a neurologist, brain MRI, and lumbar puncture. While other aetiologies are being ruled out, administer corticosteroids at a dose of 1 to 2 mg/kg/day methylprednisolone equivalents, followed by corticosteroid taper.
Permanently discontinue Opdivo for immune-related encephalitis and myasthenic syndrome/myasthenia gravis.

Complications of allogeneic haematopoietic stem cell transplant (HSCT) in classical Hodgkin lymphoma.

PD-1/PD-L1 inhibitors including nivolumab, when administered before allogeneic haematopoietic stem cell transplant (HSCT), may be associated with an increased risk of transplant-related complications, including GVHD. Fatal cases have been reported in clinical studies.
Until further data become available, careful consideration to the potential benefits of HSCT and the possible increased risk of transplant related complications should be made case by case (see Section 4.8 Adverse Effects (Undesirable Effects), Description of selected immune-related adverse reactions). Patients should be monitored closely for early evidence of transplant-related complications.

Other immune-related adverse reactions.

Other clinically significant immune-related adverse reactions, including some with fatal outcome, have been observed across clinical trials of Opdivo or Opdivo in combination with ipilimumab investigating various doses across tumour types (see Section 4.8 Adverse Effects (Undesirable Effects)).
For suspected immune-related adverse reactions, adequate evaluation should be performed to confirm aetiology or exclude other causes. Based on the severity of the adverse reaction, Opdivo monotherapy or Opdivo in combination with ipilimumab, should be withheld and corticosteroids administered. Upon improvement, Opdivo monotherapy or Opdivo in combination with ipilimumab, may be resumed after corticosteroid taper. Opdivo monotherapy or Opdivo in combination with ipilimumab, must be permanently discontinued for any severe immune-related adverse reaction that recurs and for any life-threatening immune-related adverse reaction.
Cases of myotoxicity (myositis, myocarditis, and rhabdomyolysis), some with fatal outcome, have been reported with nivolumab or nivolumab in combination with ipilimumab.
If a patient develops signs and symptoms of myotoxicity, close monitoring should be implemented, and the patient referred to a specialist for assessment and treatment without delay. Based on the severity of myotoxicity, nivolumab or nivolumab in combination with ipilimumab should be withheld or discontinued (see Section 4.2 Dose and Method of Administration), and appropriate treatment instituted.
Some cases of myocarditis can be asymptomatic, so a diagnosis of myocarditis requires a high index of suspicion. Therefore, patients with cardiac or cardio-pulmonary symptoms should undergo a prompt diagnostic workup to evaluate for myocarditis with close monitoring. Troponin is a sensitive but not diagnostic marker of myocarditis. If myocarditis is suspected, prompt initiation of a high dose of steroids (prednisone 1 to 2 mg/kg/day or methylprednisolone 1 to 2 mg/kg/day), and prompt cardiology consultation with diagnostic workup including electrocardiogram, troponin, and echocardiogram should be initiated. Additional testing may be warranted, as guided by the cardiologist, and may include cardiac magnetic resonance imaging. Once a diagnosis is established, nivolumab or nivolumab in combination with ipilimumab should be withheld. For grade 3 myocarditis, nivolumab or nivolumab in combination with ipilimumab therapy should be permanently discontinued (see Section 4.2 Dose and Method of Administration).
Cases of autoimmune haemolytic anaemia some with fatal outcome, have been reported with Opdivo or Opdivo in combination with ipilimumab (see Section 4.8 Adverse Effects (Undesirable Effects)). Patients with signs and symptoms of anaemia should undergo a prompt diagnostic workup to evaluate for autoimmune haemolytic anaemia.
Cases of Vogt-Koyanagi-Harada syndrome have been reported during postapproval use of nivolumab or nivolumab in combination with ipilimumab (see Section 4.8 Adverse Effects (Undesirable Effects), Postmarketing experience).
Solid organ transplant rejection has been reported in the postmarketing setting in patients treated with PD‐1/PD-L1 inhibitors. Treatment with nivolumab may increase the risk of rejection in solid organ transplant recipients. Consider the benefit of treatment with nivolumab versus the risk of possible organ rejection in these patients.
Rapid-onset and severe graft-versus-host disease (GVHD), some with fatal outcome, has been reported in the postmarketing setting in patients who had undergone prior allogeneic stem cell transplant and subsequently received PD-1/PD-L1 inhibitors.

Infusion reaction.

Severe infusion reactions have been reported in clinical trials of Opdivo monotherapy or Opdivo in combination with ipilimumab (see Section 4.8 Adverse Effects (Undesirable Effects)). In case of a severe or life-threatening infusion reaction, the infusion must be discontinued and appropriate medical therapy administered. Patients with mild or moderate infusion reaction may continue to receive Opdivo monotherapy or Opdivo in combination with ipilimumab with close monitoring and use of premedication according to local treatment guidelines for prophylaxis of infusion reactions.

Opdivo in combination with ipilimumab.

Review the full prescribing information for ipilimumab prior to initiation of the Opdivo in combination with ipilimumab. Both agents are associated with immune-related adverse reactions and may require immunosuppression. In clinical trials, the immune-related adverse reactions that are described in Section 4.4 Special Warnings and Precautions for Use occurred at higher frequencies when Opdivo was administered in combination with ipilimumab compared with Opdivo as a monotherapy. Most immune-related adverse reactions (except for endocrinopathies) improved or resolved with appropriate management, including initiation of corticosteroids and treatment modifications.
Patients receiving Opdivo in combination with ipilimumab should be monitored for immune-related adverse reactions clinically and with appropriate investigations prior to each dose during the combination phase.

Opdivo in combination with cabozantinib.

When nivolumab is given with cabozantinib, higher frequencies of Grades 3 and 4 ALT and AST elevations have been reported in patients with advanced RCC (see Section 4.8 Adverse Effects (Undesirable Effects)). Liver enzymes should be monitored before initiation of and periodically throughout treatment. Medical management guidelines for both medicines should be followed (see Section 4.2 Dose and Method of Administration; see Product Information for cabozantinib).

Opdivo and EGFR TKIs in NSCLC.

Opdivo is not approved for combination with epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) use in NSCLC. Serious adverse events, including deaths (one case of pneumonitis and one case of toxic epidermal necrolysis), have been reported in a Phase II non-randomised trial of nivolumab in combination with an investigational 3rd generation TKI.
In patients transitioning from an EGFR TKI to Opdivo monotherapy, a sufficient wash-out period should be observed to minimise the risk of adverse events occurring from the combination. Clinical judgement should be used to determine if any serious or clinically relevant adverse events occurring from an EGFR TKI are resolved prior to initiation of Opdivo.

Increased mortality in patients with multiple myeloma (not an approved indication) when a PD-1 blocking antibody is added to a thalidomide analogue and dexamethasone.

In randomised clinical trials in patients with multiple myeloma, the addition of a PD-1 blocking antibody, including nivolumab, to a thalidomide analogue plus dexamethasone, a use for which no PD-1 blocking antibody is indicated, resulted in increased mortality. Treatment of patients with multiple myeloma with a PD-1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials.

Patient counselling information.

Patients should be advised to report immediately any signs or symptoms suggestive of adverse reactions (see Section 4.4 Special Warnings and Precautions for Use). The importance of reporting any worsening of symptoms or severity should be emphasised. Patients should be strongly advised not to treat any of these symptoms with over-the-counter medications without consultation with a health care provider.

Patient alert card.

All prescribers of Opdivo must be familiar with the immune-related adverse reactions. The prescriber must discuss the risks of Opdivo therapy with the patient. Each patient must be provided with the Opdivo patient alert card.

Special populations.

Populations excluded from registrational clinical trials.

Populations excluded from clinical studies of Opdivo or Opdivo in combination with other therapeutic agents are listed in Table 4 according to studied indication. In the absence of data, Opdivo should be used with caution in these populations after careful consideration of the potential benefit-risk on an individual basis (also see Section 5.1 Pharmacodynamic Properties, Clinical trials).

Use in renal impairment.

The safety and efficacy of Opdivo have not been studied in patients with severe renal impairment. See Section 4.2 Dose and Method of Administration, Patients with renal impairment.

Use in hepatic impairment.

The safety and efficacy of Opdivo have not been studied in patients with severe hepatic impairment or with cirrhosis of Child-Pugh B or C severity. Opdivo must be administered with caution in these patients. Data in patients with moderate hepatic impairment are limited (see Section 5.2 Pharmacokinetic Properties; Section 4.2 Dose and Method of Administration, Patients with hepatic impairment; Section 4.8 Adverse Effects (Undesirable Effects), Description of selected immune-related adverse reactions, Immune-related hepatitis).

Patients on controlled sodium diet.

Each mL of this medicinal product contains 0.1 mmol (or 2.5 mg) sodium. To be taken into consideration when treating patients on a controlled sodium diet.

Use in the elderly.

See Section 4.2 Dose and Method of Administration.

Paediatric use.

The safety and efficacy of Opdivo for the adjuvant treatment of melanoma in paediatric patients who are at least 12 years old and weigh at least 40 kg have been established. This usage is supported by the same evidence that supports this use in adults (see Section 5.1 Pharmacodynamic Properties, Clinical trials), plus additional data analyses that suggest that at the recommended Opdivo dose, nivolumab exposures in paediatric patients 12 years of age who weigh at least 40 kg are expected to result in similar safety and efficacy to that of adults. The pharmacokinetics of monoclonal antibodies and the nature of melanoma is sufficiently similar to allow extrapolation of data from adult patients to paediatric patients 12 years of age or older (who weigh at least 40 kg).
The safety and efficacy of Opdivo in children below 12 years have not been established. No data are available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Pharmacokinetic interaction studies have not been conducted. Nivolumab is a human monoclonal antibody. As monoclonal antibodies are not metabolised by cytochrome P450 (CYP) enzymes or other drug metabolizing enzymes, inhibition or induction of these enzymes by coadministered medicinal products is not anticipated to affect the pharmacokinetics of nivolumab. Nivolumab is not expected to have an effect on CYP or other drug metabolizing enzymes in terms of inhibition or induction.

Other forms of interaction.

Systemic immunosuppression.

The use of systemic corticosteroids and other immunosuppressants at baseline, before starting nivolumab, should be avoided because of their potential interference with the pharmacodynamic activity. However, systemic corticosteroids and other immunosuppressants can be used after starting nivolumab to treat immune-related adverse reactions. The use of systemic immunosuppression after starting nivolumab treatment does not appear to impair the efficacy of nivolumab.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Studies to evaluate the effect of Opdivo on fertility have not been performed. Thus, the effect of Opdivo on male and female fertility is unknown.
(Category D)
Opdivo is not recommended during pregnancy or in women of childbearing potential not using effective contraception, unless the clinical benefit outweighs the potential risk. Advise females of reproductive potential to use effective contraception during treatment with Opdivo for at least 5 months following the last dose of Opdivo.
There are no data on the use of Opdivo in pregnant women. Human IgG4 is known to cross the placental barrier and Opdivo is an IgG4; therefore Opdivo has the potential to be transmitted from the mother to the developing foetus. It is not known whether nivolumab can cause foetal harm when administered to a pregnant woman (see Section 5.3 Preclinical Safety Data).
It is not known whether Opdivo is secreted in human breast milk. Because many drugs, including antibodies, can be secreted in human milk, a risk to newborns/infants cannot be excluded. Clinical judgement is required to determine whether to discontinue breast-feeding or to discontinue Opdivo therapy, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the mother.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects on the ability to drive and use machines have been performed. Based on its pharmacodynamic properties, Opdivo is unlikely to affect this ability. Because of potential adverse reactions such as fatigue (see Section 4.8 Adverse Effects (Undesirable Effects)), patients should be advised to use caution when driving or operating machinery until they are certain that Opdivo does not adversely affect them.

4.8 Adverse Effects (Undesirable Effects)

Nivolumab monotherapy across tumour types.

Nivolumab is most commonly associated with immune-related adverse reactions. Most of these, including severe reactions, resolved following initiation of appropriate medical therapy or withdrawal of nivolumab (see Section 4.8 Adverse Effects (Undesirable Effects), Description of selected immune-related adverse reactions).
The overall safety profile of nivolumab 3 mg/kg two weekly as monotherapy was assessed from a pooled dataset (n = 4646) which excluded study CA209040. The most frequent adverse reactions in the pooled dataset (≥ 10%) were fatigue (29.0%), rash (18.8%), pruritus (15.2%), diarrhoea (14.8%) and nausea (10.5%). The majority of adverse reactions were mild to moderate (Grade 1 or 2).
Adverse reactions reported in the pooled dataset for patients treated with nivolumab monotherapy (n = 4646) are presented in Table 5. These reactions are presented by system organ class and by frequency. Frequencies are defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000).

Classical Hodgkin lymphoma.

The safety of Opdivo 3 mg/kg every 2 weeks as monotherapy was evaluated in 266 adult patients with cHL post high-dose chemotherapy and ASCT (243 patients in study CA209205 and 23 patients in CA209039). The median number of doses was higher in the cHL nivolumab monotherapy population compared with the pooled nivolumab monotherapy population across tumours (N = 1991) (23 versus 10, respectively). The median duration of study therapy was longer in the cHL nivolumab monotherapy population compared with the pooled nivolumab monotherapy population across tumours (18.6 months versus 5.3 months, respectively). Some adverse reactions (all grades) were reported at a higher frequency in the cHL nivolumab monotherapy population compared with the pooled nivolumab monotherapy population across tumours: infusion related reaction (13.2%), lipase increased (7.1%), neutropenia (6.8%) and thrombocytopenia (6.4%). Grade 3 or 4 adverse reactions of lipase increased (3.8%) and neutropenia (3.8%) were also reported at a higher frequency in the cHL nivolumab monotherapy population. All other adverse reactions (all grades and Grade 3 or 4) were similar to the pooled nivolumab monotherapy population across tumours.

Hepatocellular carcinoma.

The safety of Opdivo was evaluated in a 154-patient subgroup of patients with HCC and Child-Pugh A cirrhosis who progressed on or were intolerant to sorafenib enrolled in an open-label trial (CA209040). Patients were required to have an AST and ALT of no more than five times the upper limit of normal and total bilirubin of less than 3 mg/dL. The median duration of exposure to Opdivo was 6 months.
The toxicity profile observed in patients with advanced HCC was generally similar to that observed in patients with other cancers, with the exception of a higher incidence of elevations in transaminases and bilirubin levels. Treatment with Opdivo resulted in treatment-emergent Grade 3 or 4 AST in 27 (18%) patients, Grade 3 or 4 ALT in 16 (11%) patients, and Grade 3 or 4 bilirubin in 11 (7%) patients. Immune-mediated hepatitis requiring systemic corticosteroids occurred in 8 (5%) patients.

Nivolumab in combination with ipilimumab across tumour types.

The overall safety profile of nivolumab in combination with ipilimumab was assessed from a pooled dataset for 448 patients treated with nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg for melanoma (studies CA209067 [combination group], CA209069, and CA209004-cohort 8) and 547 patients treated with nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg for RCC (study CA209214) and a total of 622 patients treated with nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg for OSCC (study CA209648) and MPM (study CA209743).
Adverse reactions reported in the pooled dataset for patients treated with nivolumab in combination with ipilimumab (n = 1,617) are presented in Table 6. These reactions are presented by system organ class and by frequency. Frequencies are defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000).