Consumer medicine information

Opdivo

Nivolumab

BRAND INFORMATION

Brand name

Opdivo

Active ingredient

Nivolumab

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Opdivo.

WARNINGS AND PRECAUTIONS - COMBINATION OF OPDIVO AND IPILIMUMAB

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.

WHAT IS IN THIS LEAFLET

This leaflet answers some common questions about OPDIVO. It does not contain all of the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you receiving OPDIVO against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor.

You should read this leaflet carefully and keep it in a safe place to refer to it later.

WHAT IS OPDIVO USED FOR

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

Treatment with OPDIVO

OPDIVO is used to treat advanced skin cancer (unresectable or metastatic melanoma). OPDIVO is also used to treat skin cancer (melanoma) after surgical removal of the cancer.

OPDIVO is used to treat 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) and a type of liver cancer (hepatocellulcar carcinoma) if your cancer has not responded, or if it has stopped responding, to earlier treatment.

Treatment with OPDIVO in combination with ipilimumab

OPDIVO in combination with ipilimumab is used to treat advanced melanoma in adults and a type of advanced kidney cancer (renal cell carcinoma).

Treatment with OPDIVO in combination with ipilimumab and chemotherapy

OPDIVO in combination with ipilimumab and chemotherapy is used to treat advanced lung cancer in adults.

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

OPDIVO will be given to you in hospital under the supervision of an experienced doctor.

Ask your doctor if you have any questions about why OPDIVO has been prescribed for you.

Your doctor will continue giving you OPDIVO for as long as you keep benefitting from it or until you no longer tolerate the treatment.

Patients receiving OPDIVO after surgical removal of melanoma may require treatment for no longer than one year.

BEFORE YOU ARE GIVEN OPDIVO

You should not be given OPDIVO

  • if you are allergic (hypersensitive) to nivolumab or any of the other ingredients of OPDIVO. If you are not sure, talk to your doctor.

Check with your doctor or nurse before you are given OPDIVO if:

  • you have an autoimmune disease (a condition where the body attacks its own cells) like Crohn's, ulcerative colitis or lupus;
  • you have any history of inflammation of the lungs
  • you have been told your cancer has spread to your brain
  • you have melanoma of the eye
  • you were previously given ipilimumab, another medicine for the treatment of advanced melanoma, and experienced side effects because of this medicine.
  • you 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.

OPDIVO may cause:

  • Problems with your lungs such as breathing difficulties, or cough. These may be signs of inflammation of the lungs (pneumonitis or interstitial lung disease).
  • Diarrhoea (watery, loose or soft stools) or any symptoms of inflammation of the intestines (colitis), such as stomach pain and mucus or blood in the stool.
  • Inflammation of the liver (hepatitis). Signs and symptoms of hepatitis may include abnormal liver function tests, eye or skin yellowing (jaundice), pain on the right side of your stomach area, or tiredness.
  • Inflammation or problems with your kidneys. Signs and symptoms may include abnormal kidney function tests decreased volume of urine, and kidney failure.
  • Problems with your hormone producing glands (including the thyroid, parathyroid, pituitary, and adrenal glands) that may affect how these glands work. Signs and symptoms that your glands are not working properly may include fatigue (extreme tiredness), weight change or headache, muscle aches or cramps and visual disturbances.
  • Diabetes (symptoms include 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) or diabetic ketoacidosis (acid in the blood produced from diabetes).
  • 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).
  • Loss of the covering around the nerves (demyelination), inflammation of the nerves caused by the body attacking itself, causing numbness, weakness, tingling or burning pain.
  • A condition in which the muscles become weak and tire easily (myasthenic syndrome).
  • A temporary inflammation of the nerves that causes pain, weakness and paralysis in the extremities (Guillain-Barré syndrome).
  • Inflammation of the brain
  • Inflammation of muscles causing pain or stiffness
  • Inflammation of the heart (myocarditis) characterised by shortness of breath, fatigue, palpitations or chest pain
  • Muscle breakdown/injury (rhabdomyolysis) characterised by muscle pain, weakness, nausea or vomiting.
  • Solid organ transplant rejection.

Tell your doctor immediately if you have any signs or symptoms of the possible side effects listed above or if your symptoms get worse.

Do not try to treat your symptoms with other medicines.

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.

Using other medicines

Please tell your doctor if you are taking or have recently taken any other medicines, including medicines obtained without a prescription. Ask your doctor for advice before taking any medicine during your treatment.

Children

It is not recommended to use this medicine in children or an adolescent (below 18 years) until further information becomes available.

Take special care with OPDIVO

OPDIVO is a medicine that influences your immune system and may cause inflammation in parts of your body. Inflammation can cause serious damage to your body and some inflammatory conditions may be life-threatening. 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 "Possible Side Effects".

Pregnancy and breast-feeding

Tell your doctor if you are pregnant, planning 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 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.

Driving and using machines

No studies on the effects 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.

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.

HOW OPDIVO IS 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 need.

Dosage and frequency of administration

The recommended dose and frequency 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 ipilimumab or ipilimumab and chemotherapy.

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 package leaflet of ipilimumab in order to understand the use of this medicine. If you have questions about this medicine, 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 stop using OPDIVO

Stopping your treatment may stop the effect of the medicine. Do not stop treatment with OPDIVO unless you have discussed this with your doctor.

If you have any further questions about your treatment or the use of this medicine, ask your doctor.

WHILE YOU ARE BEING TREATED WITH OPDIVO

Things you must do

Tell your doctor immediately if you have any signs or symptoms of possible side effects or if they get worse. See Possible Side Effects.

Do not try to treat your symptoms with other medicines on your own. You 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.

Tell any other doctors, dentists, 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.

Tell your doctor immediately if you develop symptoms of an allergic reaction.

These symptoms may be:

  • 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

POSSIBLE SIDE EFFECTS

Like all medicines, OPDIVO can cause side effects, although not everybody gets them. Your doctor will discuss these with you and will explain the risks and benefits of your treatment.

Do not try to treat your symptoms with other medicines.

Do not be alarmed by possible side effects. You may not experience any of them.

Ask your doctor to answer any questions you may have.

The following side effects have been reported in clinical trials when OPDIVO has been given alone:

Very common (may affect more than 1 in 10 people)

  • Decrease in some white blood cells
  • Diarrhoea (watery, loose or soft stools), nausea
  • Skin rash sometimes with blisters, itching
  • Feeling tired or weak

Common (may affect up to 1 in 10 people)

  • Infections of the upper respiratory tract
  • Underactive thyroid gland, which can cause tiredness or weight gain, overactive thyroid gland, which can cause rapid heart rate, sweating and weight loss
  • Decreased appetite
  • Inflammation of the nerves causing numbness, weakness, tingling or burning pain of the arms and legs, headaches, dizziness
  • Inflammation of the lungs (pneumonitis), characterised by coughing and difficulty breathing
  • Coughing, shortness of breath (dyspnoea)
  • Inflammation of the intestines (colitis)
  • 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)
  • Allergic reaction, reaction related to the infusion of the medicine
  • High blood pressure (hypertension)

Uncommon (may affect up to 1 in 100 people)

  • Serious lung infection (pneumonia), bronchitis
  • 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, diabetes
  • Inflammation of the pancreas, inflammation of the stomach (gastritis)
  • Dehydration
  • Increased acid level in the blood
  • Increase in some white blood cells
  • Inflammation of the eye, which causes pain and redness, blurred vision, dry eyes
  • Inflammation in the kidney, kidney failure
  • Fast heart rate
  • Arthritis
  • Damage to nerves causing numbness and weakness (polyneuropathy),inflammation of the nerves caused by the body attacking itself, causing numbness, weakness, tingling and burning pain
  • Inflammation of the liver (hepatitis)
  • Fluid around the lungs
  • 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), skin conditions of the face where the nose and cheeks are unusually red (rosacea), hives (itchy, bumpy rash)
  • Pain, chest pain

Rare (may affect up to 1 in 1000 people)

  • Life threatening allergic reaction
  • Severe and possibly fatal peeling of the skin (toxic epidermal necrolysis, Steven-Johnson syndrome)
  • Loss of the covering around the nerves (demyelination) pain
  • A condition in which the muscles become weak and tire easily (myasthenic syndrome)
  • A temporary inflammation of the nerves that causes pain, weakness and paralysis in the extremities (Guillain-Barré syndrome)
  • Inflammation of the brain
  • Ulcer of the small intestine
  • Blockage of the bile ducts
  • Fluid in lungs
  • Acid in the blood produced from diabetes (diabetic ketoacidosis)
  • A disease causing inflammation or enlargement of a lymph node (Kikuchi lymphadenitis)
  • Changes in the rhythm or rate of the heart, abnormal heart rhythm
  • Inflammation of the heart (myocarditis) characterised by shortness of breath, fatigue, palpitations or chest pain
  • Inflammation of muscles causing pain or stiffness
  • Muscle breakdown/injury (rhabdomyolysis) characterised by muscle pain, weakness, nausea or vomiting.
  • Myopathy (aching muscles, muscle tenderness or weakness, not caused by exercise)
  • Inflammatory disease of blood vessels
  • Disease in which the immune system attacks the glands that make moisture for the body, such as tears and saliva (Sjogren's syndrome)
  • decrease in parathyroid hormone
  • blood disorder caused by overactive immune cells

Changes in test results

OPDIVO may cause changes in the results of tests carried out by your doctor. These include:

  • Abnormal liver function tests
  • Abnormal kidney function tests
  • A decreased number of red blood cells (which carry oxygen), white blood cells (which are important in fighting infection) or platelets (cells which help the blood clot)
  • Abnormal levels of calcium, potassium, magnesium or sodium in your blood
  • Decrease in body weight
  • Higher levels of sugar in your blood (hyperglycaemia)

The following side effects have been reported in clinical trials when OPDIVO has been given in combination with ipilimumab:

Very common (may affect more than 1 in 10 people)

  • Overactive thyroid gland, which can cause rapid heart rate, sweating and weight loss
  • Underactive thyroid gland, which can cause tiredness or weight gain
  • Decreased appetite
  • Headache
  • Shortness of breath (dyspnoea)
  • Inflammation of the intestines (colitis), diarrhoea (watery, loose or soft stools), vomiting, nausea, stomach pain
  • Skin rash sometimes with blisters, itching
  • Pain in the joints, muscles and bones
  • Feeling tired or weak
  • Fever

Common (may affect up to 1 in 10 people)

  • Serious lung infection (pneumonia), infections of the upper respiratory tract
  • Increase in some white blood cells
  • 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; overactive thyroid gland, which can cause rapid heart rate, sweating and weight loss; inflammation of the thyroid gland (hyperthyroidism); swelling of the thyroid gland
  • Dehydration
  • Inflammation of the nerves causing numbness, weakness, tingling or burning pain of the arms and legs; dizziness
  • Inflammation of the eye, which causes pain and redness, blurred vision
  • Fast heart rate
  • High blood pressure (hypertension)
  • Inflammation of the lungs (pneumonitis), characterised by coughing and difficulty breathing, blood clots, cough
  • Mouth ulcers and cold sores (stomatitis), inflammation of the pancreas (pancreatitis), constipation, dry mouth
  • Inflammation of the liver
  • 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
  • Kidney failure (including abrupt loss of kidney function)
  • Oedema (swelling), pain
  • Allergic reaction, reactions related to the infusion of the medicine

Uncommon (may affect up to 1 in 100 people)

  • Inflammation of the brain
  • Bronchitis
  • Chronic diseases associated with a build-up of inflammatory cells in various organs and tissues, most commonly the lungs (sarcoidosis)
  • Acid in the blood produced from diabetes (diabetic ketoacidosis), diabetes
  • A temporary inflammation of the nerves that causes pain, weakness and paralysis in the extremities (Guillain-Barré syndrome); damage to nerves causing numbness and weakness (polyneuropathy); inflammation of the nerves; foot drop (peroneal nerve palsy); inflammation of the nerves caused by the body attacking itself, causing numbness, weakness, tingling or burning pain (autoimmune neuropathy)
  • Changes in the rhythm or rate of the heart beat, abnormal heart rhythm
  • Fluid around the lungs
  • Intestinal perforation, inflammation of the stomach (gastritis), inflammation of the duodenum (duodenitis)
  • Skin disease with thickened patches of red skin, often with silvery scales (psoriasis)
  • Chronic disease of joints (spondyloarthropathy)
  • Disease in which the immune system attacks the glands that make moisture for the body, such as tears and saliva (Sjogren's syndrome)
  • Inflammation of the joints (arthritis)
  • Inflammation of muscles (myositis) causing pain or stiffness
  • Inflammation of the kidney (nephritis)
  • Chest pain
  • Inflammation of the heart (myocarditis) characterised by shortness of breath, fatigue, palpitations or chest pain.
  • Muscle breakdown/injury (rhabdomyolysis) characterised by muscle pain, weakness, nausea or vomiting.

Rare (may affect up to 1 in 1000 people)

  • Severe and possibly fatal peeling of the skin (toxic epidermal necrolysis, Steven-Johnson syndrome)
  • decrease in parathyroid hormone
  • blood disorder caused by overactive immune cells

Changes in test results

OPDIVO in combination with ipilimumab may cause changes in the results of tests carried out by your doctor. These include:

  • Abnormal liver function tests
  • Abnormal kidney function tests
  • A decreased number of red blood cells (which carry oxygen), white blood cells (which are important in fighting infection) or platelets (cells which help the blood to clot)
  • An increased level of the enzyme that breaks down fats and of the enzyme that breaks down starch.
  • Abnormal levels of calcium, potassium, magnesium or sodium in your blood
  • Higher blood levels of bilirubin
  • Decrease in body weight
  • Higher (hyperglycaemia) or lower (hypoglycaemia) levels of sugar in your blood

The following side effects have been reported in clinical trials when OPDIVO has been given in combination with ipilimumab and chemotherapy:

Very common (may affect more than 1 in 10 people)

  • Underactive thyroid gland, which can cause tiredness or weight gain
  • Decreased appetite
  • diarrhoea (watery, loose or soft stools), vomiting, nausea
  • Skin rash sometimes with blisters, itching
  • Feeling tired or weak

Common (may affect up to 1 in 10 people)

  • Conjunctivitis
  • Serious lung infection (pneumonia), infections of the upper respiratory tract
  • Increase in some white blood cells
  • Allergic reaction, reactions related to the infusion of the medicine
  • Decreased secretion of hormones produced by adrenal glands (glands situated above the kidneys), inflammation (hypophysitis) of the pituitary gland situated at the base of the brain, overactive thyroid gland, which can cause rapid heart rate, sweating and weight loss, swelling of the thyroid gland
  • Inflammation of the nerves causing numbness, weakness, tingling or burning pain of the arms and legs; dizziness
  • dry eyes
  • headache
  • Shortness of breath (dyspnoea)
  • Inflammation of the lungs (pneumonitis), characterised by coughing and difficulty breathing, blood clots, cough
  • Inflammation of the intestines (colitis)
  • Mouth ulcers and cold sores (stomatitis), inflammation of the pancreas (pancreatitis), constipation, dry mouth
  • Inflammation of the liver
  • dry skin, redness of the skin, unusual hair loss or thinning
  • Pain in the joints, muscles and bones, inflammation of the joints
  • Kidney failure (including abrupt loss of kidney function)
  • Fever
  • Oedema (swelling)

Uncommon (may affect up to 1 in 100 people)

  • underactive function (hypopituitarism) of the pituitary gland situated at the base of the brain, decrease in parathyroid hormone
  • damage to nerves causing numbness and weakness (polyneuropathy); inflammation of the nerves caused by the body attacking itself, causing numbness, weakness, tingling or burning pain (autoimmune neuropathy), inflammation of the brain
  • blurred vision
  • Changes in the rhythm or rate of the heart beat, abnormal heart rhythm
  • High blood pressure (hypertension), low blood pressure (hypotension)
  • Fluid around the lungs, bronchitis
  • Skin disease with thickened patches of red skin, often with silvery scales (psoriasis)
  • Severe and possibly fatal peeling of the skin (Steven-Johnson syndrome)
  • Inflammation of muscles (myositis) causing pain or stiffness
  • Inflammation of the kidney (nephritis)
  • Chest pain
  • Changes in test results
  • OPDIVO in combination with ipilimumab and chemotherapy may cause changes in the results of tests carried out by your doctor. These include:
    - Abnormal liver function tests
    - Abnormal kidney function tests
    - A decreased number of red blood cells (which carry oxygen), white blood cells (which are important in fighting infection) or platelets (cells which help the blood to clot)
    - An increased level of the enzyme that breaks down fats and of the enzyme that breaks down starch.
    - Abnormal levels of calcium, potassium, magnesium or sodium in your blood
    - Higher levels of sugar in your blood (hyperglycaemia)
    - Higher blood levels of bilirubin

FURTHER INFORMATION

What OPDIVO contains

  • The active substance is nivolumab.
    Each vial contains either 40 mg (in 4mL) or 100 mg (in 10mL) of nivolumab.
  • The other ingredients are sodium citrate dihydrate, sodium chloride, mannitol (E421), pentetic acid, polysorbate 80, sodium hydroxide, hydrochloric acid and water for injection.

What OPDIVO looks like and contents of the pack

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

It is available in packs containing either 1 vial of 40 mg in 4 mL or 1 vial of 100 mg in 10 mL.

HOW TO STORE OPDIVO

It is unlikely that you will be asked to store OPDIVO yourself. It will be stored in the hospital or clinic where it is given to you.

Sponsored by

Bristol-Myers Squibb Australia Pty Ltd
4 Nexus Court, Mulgrave
Victoria 3170, Australia,

Registration Numbers:

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).

Date of preparation:

July 2020

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

Published by MIMS September 2020

BRAND INFORMATION

Brand name

Opdivo

Active ingredient

Nivolumab

Schedule

S4

 

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 patients with melanoma with involvement of lymph nodes or metastatic disease who have undergone complete resection.
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 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.

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, 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 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.

4.2 Dose and Method of Administration

Treatment must be initiated and supervised by specialist physicians experienced in the treatment of cancer.
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 1. Detailed guidelines for the management of immune-related adverse reactions are described, see 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.

Opdivo monotherapy.

Unresectable or metastatic melanoma, squamous NSCLC, non squamous NSCLC, renal cell carcinoma, relapsed/refractory classical Hodgkin lymphoma, recurrent or metastatic squamous cell carcinoma of the head and neck, urothelial carcinoma, melanoma with involvement of lymph nodes or metastatic disease after complete resection and hepatocellular carcinoma.

The recommended dose of Opdivo as a monotherapy administered intravenously over 30 minutes is 3 mg/kg every 2 weeks or 240 mg every 2 weeks or 480 mg every 4 weeks. Treatment should be continued as long as clinical benefit is observed or until treatment is no longer tolerated by the patient.
The maximum treatment duration with Opdivo as monotherapy for adjuvant melanoma is 12 months.

Opdivo in combination with ipilimumab.

Opdivo and ipilimumab should be administered and monitored under the supervision of physicians experienced with the use of immunotherapy.
Please review the full prescribing information for ipilimumab prior to initiation of Opdivo in combination with ipilimumab.
In the initial combination phase, administer Opdivo and ipilimumab on the same day. Use separate infusion bags and filters for each infusion. Administer Opdivo first followed by ipilimumab, after completion of the Opdivo infusion.

Unresectable or metastatic melanoma.

Combination phase.

The recommended dose of Opdivo in the combination phase is 1 mg/kg administered intravenously over 30 minutes every 3 weeks for the first 4 doses in combination with ipilimumab 3 mg/kg administered intravenously over 90 minutes. This should be followed by Opdivo monotherapy therapy in the single-agent phase (see below).

Single-agent phase.

The recommended dose of Opdivo in the single-agent phase administered intravenously over 30 minutes is 3 mg/kg every 2 weeks or 240 mg every 2 weeks or 480 mg every 4 weeks. Following the last dose of the combination of nivolumab and ipilimumab, the first dose of nivolumab monotherapy should be administered after 3 weeks when using 3 mg/kg or 240 mg or 6 weeks when using 480 mg.
Treatment with Opdivo in the single-agent phase should be continued as long as clinical benefit is observed or until treatment is no longer tolerated by the patient.

RCC.

Combination phase.

The recommended dose of Opdivo in the combination phase is 3 mg/kg administered intravenously over 30 minutes every 3 weeks for the first 4 doses in combination with 1 mg/kg ipilimumab administered intravenously over 30 minutes. This should be followed by Opdivo monotherapy therapy in the single-agent phase (see below).

Single-agent phase.

The recommended dose of Opdivo in the single agent phase administered intravenously over 30 minutes is 3 mg/kg every 2 weeks or 240 mg every 2 weeks or 480 mg every 4 weeks. Following the last dose of the combination of nivolumab and ipilimumab, the first dose of nivolumab monotherapy should be administered after 3 weeks when using 3 mg/kg or 240 mg or 6 weeks when using 480 mg.
Treatment with Opdivo in the single-agent phase should be continued as long as clinical benefit is observed or until treatment is no longer tolerated by the patient.

NSCLC.

The recommended dose is 360 mg Opdivo administered as an intravenous infusion every 3 weeks in combination with 1 mg/kg ipilimumab administered as an intravenous infusion every 6 weeks, and platinum chemotherapy administered every 3 weeks. After completion of 2 cycles of chemotherapy, treatment is continued with 360 mg Opdivo administered as an intravenous infusion every 3 weeks in combination with 1 mg/kg ipilimumab every 6 weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

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

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

Special populations.

Paediatric patients.

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

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 in 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.
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 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 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, see Section 6.1.

4.4 Special Warnings and Precautions for Use

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 or Opdivo in combination with ipilimumab.
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 Vogt-Koyanagi-Harada syndrome have been reported during post approval 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 (see 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 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 Management Guide. 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 ipilimumab are listed in Table 2 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 (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 in children below 18 years have not been established. The use of Opdivo in children or adolescents is not recommended.

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 = 2578) across tumour types (melanoma: CA209066, CA209037, CA209067 [monotherapy group only], SQ NSCLC: CA209017, CA209063, NSQ NSCLC: CA209057, RCC: CA209025, cHL: CA209205 and CA209039; SCCHN: CA209141 and UC: CA209275 and CA209032). The most frequent adverse reactions in the pooled dataset (≥ 10%) were fatigue (30%), rash (17%), pruritus (13%), diarrhoea (13%) and nausea (12%). 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 = 2578) are presented in Table 3. 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).
A summary of laboratory abnormalities that worsened from baseline in the pooled dataset for patients treated with nivolumab monotherapy is presented in Table 4.

Adjuvant melanoma.

In the dataset of nivolumab 3 mg/kg as monotherapy for the adjuvant treatment of melanoma (n = 452), the most frequent adverse reactions (≥ 10%) were fatigue (46%), rash (29%), diarrhoea (24%), pruritus (23%), nausea (15%), arthralgia (13%), musculoskeletal pain (11%), and hypothyroidism (11%). The majority of adverse reactions were mild to moderate (Grade 1 or 2).
The overall safety profile of Opdivo 3 mg/kg for the treatment of adjuvant melanoma was consistent with that established across tumour types for nivolumab monotherapy.

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).
Adverse reactions reported in the pooled dataset for patients treated with nivolumab in combination with ipilimumab (n = 995) 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).
A summary of laboratory abnormalities that worsened from baseline in the pooled dataset for patients treated with nivolumab in combination with ipilimumab is presented in Table 6.

Melanoma.

In the pooled dataset of nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg in melanoma (CA209067 [combination group], CA209069, and CA209004-cohort 8), the most frequent adverse reactions (≥ 10%) were rash (52%), fatigue (46%), diarrhoea (43%), pruritus (36%), nausea (26%), pyrexia (19%), decreased appetite (16%), hypothyroidism (16%), colitis (15%), vomiting (14%), abdominal pain (13%), arthralgia (13%), headache (11%) and dyspnoea (10%). The majority of adverse reactions were mild to moderate (Grade 1 or 2).
Among the 313 patients treated with nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg in CA209067, 154/313 (49%) had the first onset of Grade 3 or 4 adverse reactions during the initial combination phase. Among the 147 patients in this group who continued treatment in the single-agent phase, 47 (32%) experienced at least one Grade 3 or 4 adverse reaction during the single-agent phase.

RCC.

In the CA209214 dataset of nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg in RCC (n = 547), with a minimum follow-up of 17.5 months, the most frequent adverse reactions (≥ 10%) were fatigue (48%), rash (34%), pruritus (28%), diarrhoea (27%), nausea (20%), hypothyroidism (16%), musculoskeletal pain (15%), arthralgia (14%), decreased appetite (14%), pyrexia (14%), vomiting (11%), hyperthyroidism (11%). The majority of adverse reactions were mild to moderate (Grade 1 or 2).
Among the patients treated with nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg in CA209214, 169/547 (31%) had the first onset of Grade 3 or 4 adverse reactions during the initial combination phase. Among the 382 patients in this group who continued treatment in the single-agent phase, 144 (38%) experienced at least one Grade 3 or 4 adverse reaction during the single-agent phase.
The majority of drug-related adverse reactions observed in patients in CA209214 were generally lower in frequency and severity compared to the pooled nivolumab in combination with ipilimumab data from melanoma studies, which utilised a higher ipilimumab dose and regimen (nivolumab 1 mg/kg + ipilimumab 3 mg/kg Q3W).

Nivolumab in combination with ipilimumab and platinum-doublet chemotherapy.

NSCLC.

In the dataset of nivolumab 360 mg in combination with ipilimumab 1 mg/kg and platinum-doublet chemotherapy in NSCLC (n = 358), the most frequent adverse reactions (≥ 10%) were fatigue (36%), nausea (26%), rash (25%), diarrhoea (20%), pruritus (18%), decreased appetite (16%), hypothyroidism (15%) and vomiting (13%). The majority of adverse reactions were mild to moderate (Grade 1 or 2). Median duration of therapy was 6.1 months (95% CI 4.93, 7.06) for nivolumab in combination with ipilimumab and 2.4 months (95% CI 2.30, 2.83) for platinum-based chemotherapy.
Adverse reactions reported in the dataset for patients treated with nivolumab in combination with ipilimumab and platinum-based chemotherapy (n = 358) are presented in Table 7 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).
A summary of laboratory abnormalities that worsened from baseline in the dataset for patients treated with nivolumab in combination with ipilimumab and platinum-doublet chemotherapy is presented in Table 8.

Description of selected immune-related adverse reactions.

Both Opdivo and Opdivo in combination with ipilimumab are associated with immune-related adverse reactions. With appropriate medical therapy, these resolved in most cases.
The management guidelines for these adverse reactions are described (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use).

Note.

Time to resolution may include censored observations.

Immune-related pneumonitis.

Opdivo monotherapy.

In the pooled analysis in patients treated with nivolumab monotherapy, the incidence of pneumonitis, including interstitial lung disease and lung infiltration, was 3.4% (87/2578). The majority of cases were Grade 1 or 2 in severity reported in 0.8% (21/2578) and 1.7% (44/2578) of patients respectively. Grade 3 and 4 cases were reported in 0.7% (19/2578) and < 0.1 (1/2578) of patients respectively. Two Grade 5 cases (< 0.1%) were reported in these studies. One patient with Grade 3 pulmonary embolism and Grade 3 pneumonitis died in the SCCHN clinical trial. Median time to onset was 3.6 months (range: 0.2-19.6). Thirty-one patients (1.2%), required permanent discontinuation of nivolumab. Sixty patients received high-dose corticosteroids (at least 40 mg prednisone equivalents). Resolution occurred in 63 patients (72%) with a median time to resolution of 6.1 weeks (range: 0.1-96.7).

Opdivo in combination with ipilimumab.

In patients treated with nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg in melanoma, the incidence of pneumonitis including interstitial lung disease, was 7.8% (35/448). Grade 2, Grade 3, and Grade 4 cases were reported in 4.7% (21/448), 1.1% (5/448), and 0.2% (1/448) of patients, respectively. One of the Grade 3 pneumonitis cases worsened over 11 days with a fatal outcome. Median time to onset was 2.6 months (range: 0.7-12.6). Nine patients (2.0%) required permanent discontinuation of nivolumab in combination with ipilimumab. Twenty-one patients received high-dose corticosteroids (at least 40 mg prednisone equivalents). Resolution occurred in 29 patients (87.9%) with a median time to resolution of 6.1 weeks (range: 0.3-46.9).
In patients treated with nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg in RCC, the incidence of pneumonitis including interstitial lung disease was 6.2% (34/547). Grade 2 and Grade 3 cases were reported in 3.1% (17/547) and 1.1% (6/547), of patients, respectively. No Grade 4 or 5 cases were reported in this study. Median time to onset was 2.6 months (range: 0.25-20.6). Twelve patients (2.2%) required permanent discontinuation of nivolumab in combination with ipilimumab. Fifty-nine patients received high-dose corticosteroids (at least 40 mg prednisone equivalents). Resolution occurred in 31 patients (91.2%) with a median time to resolution of 6.1 weeks (range: 4.3-11.4).

Opdivo in combination with ipilimumab and platinum-based chemotherapy.

In patients treated with nivolumab 360 mg in combination with ipilimumab 1 mg/kg and chemotherapy in NSCLC, the incidence of pneumonitis including interstitial lung disease was 5.3% (19/358). Grade 2, Grade 3, and Grade 4 cases were reported in 2.2% (8/358), 1.1% (4/358), 0.6% (2/358) and of patients, respectively. No Grade 5 cases were reported. Median time to onset was 18.1 weeks (range: 0.6-52.4). Resolution occurred in 14 patients (74%) with a median time to resolution of 4.3 weeks (range: 0.7-27.9+).

Immune-related colitis.

Opdivo monotherapy.

In the pooled analysis in patients treated with nivolumab monotherapy, the incidence of diarrhoea, colitis or frequent bowel movements was 13.1% (339/2578). The majority of cases were Grade 1 or 2 in severity reported in 8.5% (220/2578) and 3.0% (78/2578) of patients respectively. Grade 3 cases were reported in 1.6% (41/2578) of patients. No Grade 4 or 5 cases were reported. Median time to onset was 1.8 months (range: 1 day-26.6 months). Twenty patients (0.8%) required permanent discontinuation of nivolumab. Forty-nine patients received high-dose corticosteroids (at least 40 mg prednisone equivalents). Resolution occurred in 296 patients (88%) with a median time to resolution of 2.1 weeks (range: 0.1-124.4).

Opdivo in combination with ipilimumab.

In patients treated with nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg in melanoma, the incidence of diarrhoea or colitis was 46.7% (209/448). Grade 2, Grade 3, and Grade 4 cases were reported in 13.6% (61/448), 15.8% (71/448), and 0.4% (2/448) of patients, respectively. No deaths due to diarrhoea or colitis were reported. Median time to onset was 1.2 months (range: 0.0-22.61). Seventy-one patients (15.8%) required permanent discontinuation of nivolumab in combination with ipilimumab. Ninety-six patients received high-dose corticosteroids (at least 40 mg prednisone equivalents). Resolution occurred in 184 patients (90.6%) with a median time to resolution of 3.0 weeks (range: 0.1-78.7).
In patients treated with nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg in RCC, the incidence of diarrhoea or colitis was 28.2% (154/547). Grade 2 and Grade 3 cases were reported in 10.4% (57/547) and 4.9% (27/547) of patients, respectively. No Grade 4 or 5 cases were reported. Median time to onset was 1.2 months (range: 0.0-24.7). Twenty-two patients (4.0%) required permanent discontinuation of nivolumab in combination with ipilimumab. Twenty-six patients received high-dose corticosteroids (at least 40 mg prednisone equivalents). Resolution occurred in 140 patients (91.5%) with a median time to resolution of 2.4 weeks (range: 01-103.1).

Opdivo in combination with ipilimumab and platinum-based chemotherapy.

In patients treated with nivolumab 360 mg in combination with ipilimumab 1 mg/kg and chemotherapy in NSCLC, the incidence of diarrhoea or colitis was 22.3% (80/358). Grade 2, Grade 3, Grade 4, and Grade 5 cases were reported in 7% (25/358), 5% (18/358), 0.3% (1/358), and 0.3% (1/358) of patients, respectively. Median time to onset was 5.1 weeks (range: 0.1-53.6). Resolution occurred in 70 patients (87.5%) with a median time to resolution of 1.4 weeks (range: 0.1-76.9+).

Immune-related hepatitis.

Opdivo monotherapy.

In the pooled analysis in patients treated with nivolumab monotherapy, the incidence of liver function test abnormalities was 6.7% (173/2578). The majority of cases were Grade 1 or 2 in severity reported in 3.5% (91/2578) and 1.2% (32/2578) of patients respectively. Grade 3 and 4 cases were reported in 1.6% (41/2578) and 0.3% (9/2578) of patients, respectively. No deaths due to liver function abnormalities were reported. Median time to onset was 2.1 months (range: 1 day - 27.6 months). Twenty-seven (1.0%) required permanent discontinuation of nivolumab. Thirty-six patients (1.4%) received high-dose corticosteroids (at least 40 mg prednisone equivalents). Resolution occurred in 132 patients (77%) with a median time to resolution of 9 weeks (range: 0.1-82.6).
Safety data for the HCC indication are limited to a cohort of 154 patients with Child-Pugh A disease and WHO PS 0-1. Close monitoring is recommended in patients with cirrhosis, in case immune-related hepatitis might precipitate decompensation.

Opdivo in combination with ipilimumab.

In patients treated with nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg in melanoma, the incidence of liver function test abnormalities was 29.5% (132/448). Grade 2, Grade 3, and Grade 4 cases were reported in 6.7% (30/448), 15.4% (69/448), and 1.8% (8/448) of patients, respectively. No deaths due to liver function abnormalities were reported. Median time to onset was 1.5 months (range: 0.0-30.1). Forty-one patients (9.2%) required permanent discontinuation of nivolumab in combination with ipilimumab. Fifty-eight patients received high-dose corticosteroids (at least 40 mg prednisone equivalents). Resolution occurred in 116 patients (92.8%) with a median time to resolution of 5.0 weeks (range: 0.1-53.1).
In patients treated with nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg in RCC, the incidence of liver function test abnormalities was 18.5% (101/547). Grade 2, Grade 3, and Grade 4 cases were reported in 4.8% (26/547), 6.6% (36/547), and 1.6% (9/547) of patients, respectively. No Grade 5 cases were reported. Median time to onset was 2.0 months (range: 0.4-26.8). Twenty-four patients (4.4%) required permanent discontinuation of nivolumab in combination with ipilimumab. Thirty-five patients received high-dose corticosteroids (at least 40 mg prednisone equivalents). Resolution occurred in 86 patients (85.1%) with a median time to resolution of 6.1 weeks (range: 0.1-82.9).

Opdivo in combination with ipilimumab and platinum-based chemotherapy.

In patients treated with nivolumab 360 mg in combination with ipilimumab 1 mg/kg and chemotherapy in NSCLC, the incidence of liver function test abnormalities was 13.4% (48/358). Grade 2, Grade 3, and Grade 4 cases were reported in 3.1% (11/358), 3.4% (12/358), and 1.1% (4/358) of patients, respectively. No Grade 5 cases were reported. Median time to onset was 10.6 weeks (range: 1.1-68.3). Resolution occurred in 37 patients (80.4%) with a median time to resolution of 5 weeks (range: 0.3+-45.0+).

Immune-related nephritis and renal dysfunction.

Opdivo monotherapy.

In the pooled analysis in patients treated with nivolumab monotherapy, the incidence of nephritis and renal dysfunction was 2.8% (71/2578). The majority of cases were Grade 1 or 2 in severity reported in 1.6% (41/2578) and 0.7% (18/2578) of patients respectively. Grade 3 and 4 cases were reported in 0.4% (11/2578) and < 0.1% (1/2578) of patients, respectively. No Grade 5 nephritis or renal dysfunction was reported in these studies. Median time to onset was 2.3 months (range: 1 day - 18.2 months). Seven patients (0.3%), required permanent discontinuation of nivolumab. Nineteen patients received high-dose corticosteroids (at least 40 mg prednisone equivalents). Resolution occurred in 42 patients (62%) with a median time to resolution of 12.1 weeks (range: 0.3-79.1).

Opdivo in combination with ipilimumab.

In patients treated with nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg in melanoma, the incidence of nephritis or renal dysfunction was 5.1% (23/448). Grade 2, Grade 3, and Grade 4 cases were reported in 1.6% (7/448), 0.9% (4/448), and 0.7% (3/448) of patients, respectively. No deaths due to nephritis or renal dysfunction were reported. Median time to onset was 2.6 months (range: 0.5-21.8). Four patients (0.9%) required permanent discontinuation of nivolumab in combination with ipilimumab. Four patients received high-dose corticosteroids (at least 40 mg prednisone equivalents). Resolution occurred in 17 patients (89.5%) with a median time to resolution of 1.9 weeks (range: 0.4-42.6).
In patients treated with nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg in RCC, the incidence of nephritis or renal dysfunction was 8.8% (48/547). Grade 2, Grade 3, and Grade 4 cases were reported in 4.4% (24/547), 0.7% (4/547), and 0.5% (3/547) of patients, respectively. No Grade 5 cases were reported. Median time to onset was 2.1 months (range: 0.0-16.1). Seven patients (1.3%) required permanent discontinuation of nivolumab in combination with ipilimumab. Twenty-seven patients received high-dose corticosteroids (at least 40 mg prednisone equivalents). Resolution occurred in 37 patients (77.1%) with a median time to resolution of 13.2 weeks (range: 4.1-21.1).

Opdivo in combination with ipilimumab and platinum-based chemotherapy.

In patients treated with nivolumab 360 mg in combination with ipilimumab 1 mg/kg and chemotherapy in NSCLC, the incidence of nephritis or renal dysfunction was 7% (25/358). Grade 2, Grade 3, and Grade 4 cases were reported in 2.2% (8/358), 1.7% (6/358), and 0.6 (2/358) of patients, respectively. No Grade 5 cases were reported. Median time to onset was 10.6 weeks (range: 0.1-51.3). Resolution occurred in 14 patients (56%) with a median time to resolution of 6.3 weeks (range: 0.1+-82.9+).

Immune-related endocrinopathies.

Opdivo monotherapy.

In the pooled analysis in patients treated with nivolumab monotherapy, the incidence of thyroid disorders including hypothyroidism or hyperthyroidism was 9.6% (248/2578). The majority of cases were Grade 1 or 2 in severity reported in 4.2% (107/2578) and 5.4% (139/2578) of patients respectively. Grade 3 thyroid disorders were reported in < 0.1% (2/2578) of patients. Hypophysitis (1 Grade 1; 2 Grade 2, 5 Grade 3 and 1 Grade 4), hypopituitarism (4 Grade 2 and 1 Grade 3), adrenal insufficiency (1 Grade 1; 9 Grade 2; and 5 Grade 3), diabetes mellitus (3 Grade 2 and 1 Grade 3), and diabetic ketoacidosis (2 Grade 3) were also reported. No Grade 5 endocrinopathies were reported. Median time to onset of these endocrinopathies was 2.8 months (range: 0.3-29.1). Three patients (0.1%) required permanent discontinuation of nivolumab. Eighteen patients received high dose corticosteroids (at least 40 mg prednisone equivalents). Resolution occurred in 117 patients (43%). Time to resolution ranged from 0.4 to 144 weeks.

Opdivo in combination with ipilimumab.

In patients treated with nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg in melanoma, the incidence of thyroid disorders was 25.2% (113/448). Grade 2 and Grade 3 thyroid disorders were reported in 14.5% (65/448) and 1.3% (6/448) of patients, respectively. Grade 2 and Grade 3 hypophysitis (including lymphocytic hypophysitis) occurred in 5.8% (26/448) and 2.0% (9/448) of patients, respectively. Grade 2 and Grade 3 hypopituitarism occurred in 0.4% (2/448) and 0.7% (3/448) of patients, respectively. Grade 2, Grade 3, and Grade 4 adrenal insufficiency (including secondary adrenocortical insufficiency) occurred in 1.6% (7/448), 1.3% (6/448) and 0.2% (1/448) of patients respectively. Grade 1, Grade 2, Grade 3 and Grade 4 diabetes mellitus and Grade 4 diabetic ketoacidosis were each reported in 0.2% (1/448) of patients. No deaths due to endocrinopathy were reported. Median time to onset of these endocrinopathies was 1.9 months (range: 0.0-28.1). Eleven patients (2.5%) required permanent discontinuation of nivolumab in combination with ipilimumab. Thirty-six patients received high dose corticosteroids (at least 40 mg prednisone equivalents). Resolution occurred in 59 patients (45.0%). Time to resolution ranged from 0.4 to 74.4 weeks.
In patients treated with nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg in RCC, the incidence of thyroid disorders was 27.2% (149/547). Grade 2 and Grade 3 thyroid disorders were reported in 15.7% (86/547) and 1.3% (7/547) of patients, respectively. Hypophysitis occurred in 4.0% (22/547) of patients. Grade 2, Grade 3, and Grade 4 cases were reported in 0.5% (3/547), 2.4% (13/547), and 0.4% (2/547) of patients, respectively. Grade 2 hypopituitarism occurred in 0.4% (2/547) of patients. Grade 2, Grade 3, and Grade 4 adrenal insufficiency (including secondary adrenocortical insufficiency) occurred in 2.9% (16/547), 2.2% (12/547) and 0.4% (2/547) of patients, respectively. Diabetes mellitus including Type 1 diabetes mellitus (3 Grade 2, 2 Grade 3, and 3 Grade 4), and diabetic ketoacidosis (1 Grade 4) were reported. No Grade 5 endocrinopathy was reported. Median time to onset of these endocrinopathies was 1.9 months (range: 0.0-22.3). Three patients (2.9%) required permanent discontinuation of nivolumab in combination with ipilimumab. Twenty-five patients received high-dose corticosteroids (at least 40 mg prednisone equivalents). Resolution occurred in 71 patients (42.7%) with a median time to resolution of 0.4 to 130.3 weeks.

Opdivo in combination with ipilimumab and platinum-based chemotherapy.

In patients treated with nivolumab 360 mg in combination with ipilimumab 1 mg/kg and chemotherapy in NSCLC, the incidence of thyroid disorders was 24% (86/358). Grade 2 and Grade 3 thyroid disorders were reported in 12.3% (44/358) and 0.3% (1/358) of patients, respectively. Hypophysitis occurred in 1.4% (5/358) of patients. Grade 2 and Grade 3 cases were reported in 0.6% (2/358) and 0.8% (3/358) of patients, respectively. Grade 2 hypopituitarism occurred in 0.3% (1/358) of patients. Grade 2 and Grade 3 adrenal insufficiency occurred in 1.7% (6/358) and 1.4% (5/358) of patients, respectively. Diabetes mellitus including Type 1 diabetes mellitus was not reported. No Grade 5 endocrinopathy was reported. Median time to onset of these endocrinopathies was 12.1 weeks (range:1.9-58.3). Resolution occurred in 30 patients (35.3%). Time to resolution ranged from 1.4 to 72.4+ weeks.

Immune-related skin adverse reactions.

Opdivo monotherapy.

In the pooled analysis in patients treated with nivolumab monotherapy, the incidence of rash was 26.4% (680/2578). The majority of cases were Grade 1 in severity reported in 20.1% (518/2578) of patients. Grade 2 and Grade 3 cases were reported in 5.1% (131/2578) and 1.2% (31/2578) of patients, respectively. No Grade 4 or 5 cases were reported. Median time to onset was 1.4 months (range: 1 day - 27.9 months). Eight patients (0.3%) required permanent discontinuation of nivolumab. Twenty-eight patients received high dose corticosteroids (at least 40 mg prednisone equivalents). Resolution occurred in 428 patients (64%) with a median time to resolution of 17.1 weeks (0.1-150.0).

Opdivo in combination with ipilimumab.

In patients treated with nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg in melanoma, the incidence of rash was 65% (291/448). Grade 2 and Grade 3 cases were reported in 20.3% (91/448) and 7.6% (34/448) of patients, respectively. No Grade 4 or 5 cases were reported. Median time to onset was 0.5 months (range: 0.0-19.4). Three patients (0.7%) required permanent discontinuation of nivolumab in combination with ipilimumab. Twenty patients received high dose corticosteroids (at least 40 mg prednisone equivalents). Resolution occurred in 192 patients (67.6%) with a median time to resolution of 10.4 weeks (range: 0.1-74.0).
In patients treated with nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg in RCC, the incidence of rash was 48.8% (267/547). Grade 2 and Grade 3 cases were reported in 13.7% (75/547) and 3.7% (20/547) of patients, respectively. No Grade 4 or 5 cases were reported. Median time to onset was 0.9 months (range: 0.0-17.9). Eight patients (1.5%) required permanent discontinuation of nivolumab in combination with ipilimumab. Seven patients received high-dose corticosteroids (at least 40 mg prednisone equivalents). Resolution occurred in 192 patients (72.2%) with a median time to resolution of 11.6 weeks (range: 8.7-17.1).

Opdivo in combination with ipilimumab and platinum-based chemotherapy.

In patients treated with nivolumab 360 mg in combination with ipilimumab 1 mg/kg and chemotherapy in NSCLC, the incidence of rash was 37.7% (135/358). Grade 2, Grade 3, and Grade 4 cases were reported in 11.5% (41/358), 4.2% (14/358), and 0.3% (1/358) of patients, respectively. No Grade 5 cases were reported. Median time to onset was 3.3 weeks (range: 0.1-83.1). Resolution occurred in 96 patients (71.6%) with a median time to resolution of 9.4 weeks (range: 0.1+-84.1+).

Infusion reactions.

Opdivo monotherapy.

In the pooled analysis in patients treated with nivolumab monotherapy, the incidence of hypersensitivity/infusion reactions, including anaphylactic reaction, was 4.7% (121/2578), including 6 Grade 3 (0.2%) and 2 Grade 4 (< 0.1%) cases. No deaths due to infusion reactions were reported.

Opdivo in combination with ipilimumab.

In patients treated with nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg in melanoma, the incidence of hypersensitivity/infusion reactions was 3.8% (17/448); all were Grade 1 or 2 in severity. Grade 2 cases were reported in 2.2% (10/448) of patients. No Grade 3-5 cases were reported.
In patients treated with nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg in RCC, the incidence of hypersensitivity/infusion reactions was 4.0% (22/547); all were Grade 1 or 2 in severity. Grade 2 cases were reported in 2.4% (13/547) of patients. No Grade 3-5 cases were reported.

Opdivo in combination with ipilimumab and platinum-based chemotherapy.

In patients treated with nivolumab 360 mg in combination with ipilimumab 1 mg/kg and chemotherapy in NSCLC, the incidence of hypersensitivity/infusion reactions was 4.7% (17/358). Grade 2, Grade 3, and Grade 4 cases were reported in 2.2% (8/358), 0.3% (1/358), and 0.3% (1/358) of patients, respectively. No Grade 5 cases were reported.

Immune-related neurological adverse reactions.

The following adverse events observed across clinical trials of nivolumab or nivolumab in combination with ipilimumab were reported in less than 1% of patients: demyelination, autoimmune neuropathy (including facial and abducens nerve paresis), Guillain Barré syndrome, myasthenic syndrome/myasthenia gravis, and encephalitis.

Complications of allogeneic HSCT in classical Hodgkin lymphoma.

In 49 evaluated patients from two cHL studies who underwent allogeneic HSCT after discontinuing nivolumab monotherapy, Grade 3 or 4 acute GVHD was reported in 13/49 patients (26.5%). Hyperacute GVHD, defined as acute GVHD occurring within 14 days after stem cell infusion, was reported in three patients (6%). A steroid-requiring febrile syndrome, without an identified infectious cause, was reported in six patients (12%) within the first 6 weeks post-transplantation, with five patients responding to steroids. Hepatic veno-occlusive disease occurred in one patient, who died of GVHD and multi-organ failure. Nine of 49 patients (18.4%) died from complications of allogeneic HSCT after nivolumab. The 49 patients had a median follow-up from subsequent allogeneic HSCT of 5.6 months (range: 0-19 months).

Other immune-related adverse reactions.

Other clinically significant immune-related adverse reactions have been observed. Some of these have had fatal outcome. Across clinical trials of nivolumab or nivolumab in combination with ipilimumab investigating various doses and tumour types, the following immune-related adverse reactions were reported in less than 1% of patients: pancreatitis, uveitis, gastritis, sarcoidosis, duodenitis, aseptic meningitis, myositis, myocarditis, and rhabdomyolysis.

Postmarketing experience.

The following events have been identified during post approval use of nivolumab or nivolumab in combination with ipilimumab. Because reports are voluntary from a population of unknown size, an estimate of frequency cannot be made.

Eye disorders.

Vogt-Koyanagi-Harada syndrome.

Immune-system disorders.

Solid organ transplant rejection, graft-versus-host-disease, haemophagocytic lymphohistiocytosis.

Endocrine system disorders.

Hypoparathyroidism.

Blood and lymphatic disorders.

Autoimmune anaemia, haemolytic anaemia.

Reporting suspected adverse reactions.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at http://www.tga.gov.au/reporting-problems.

4.9 Overdose

There is no information on overdosage with Opdivo.
In case of overdosage, patients must be closely monitored for signs or symptoms of adverse reactions, and appropriate symptomatic treatment instituted.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Nivolumab is a fully human immunoglobulin G4 (IgG4) monoclonal antibody (HuMAb) which binds to programmed death-1 (PD-1) receptor and blocks its interaction with the ligands PD-L1 and PD-L2. The PD-1 receptor is a negative regulator of T-cell activity. Engagement of PD-1 with PD-L1 and PD-L2, which are expressed in antigen presenting cells and may be expressed by tumours or other cells in the tumour microenvironment, results in inhibition of T-cell proliferation and cytokine secretion. Nivolumab potentiates T-cell responses, including anti-tumour responses, through blockade of PD-1 binding to PD-L1 and PD-L2 ligands. In syngeneic mouse models, blocking PD-1 activity resulted in decreased tumour growth.
Combined nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4) mediated inhibition results in enhanced T-cell function that is greater than the effects of either antibody alone, and results in improved anti-tumour responses in metastatic melanoma. In murine syngeneic tumour models, dual blockade of PD-1 and CTLA-4 resulted in synergistic anti-tumour activity.

Clinical trials.

Melanoma.

Adjuvant melanoma - Opdivo monotherapy.

Randomised phase 3 study of nivolumab vs ipilimumab 10 mg/kg (CA209238).

The safety and efficacy of nivolumab 3 mg/kg as a monotherapy for the treatment of patients with completely resected melanoma were evaluated in a phase 3, randomised, double-blind study (CA209238). The protocol allowed for the inclusion of patients (15 years or older), who had an ECOG performance status score of 0 or 1, with Stage IIIB/C or Stage IV American Joint Committee on Cancer (AJCC), 7th edition, histologically confirmed melanoma that is completely surgically resected. Per the AJCC 8th edition, this corresponds to patients with lymph node involvement (Stage III) or metastases (Stage IV). Patients were enrolled regardless of their tumour PD-L1 status. Patients with prior autoimmune disease, and any condition requiring systemic treatment with either corticosteroids (≥ 10 mg daily prednisone or equivalent) or other immunosuppressive medications, as well as patients with prior therapy for melanoma except surgery, adjuvant radiotherapy after neurosurgical resection for lesions of the central nervous system, and prior adjuvant interferon completed ≥ 6 months prior to randomisation were excluded from the study.
A total of 906 patients were randomised to receive either nivolumab 3 mg/kg (n = 453) administered every 2 weeks or ipilimumab 10 mg/kg (n = 453) administered every 3 weeks for 4 doses then every 12 weeks beginning at week 24 for up to 1 year. Ipilimumab (10 mg/kg) was chosen as the comparator as it has demonstrated a superior overall survival (OS) compared to standard of care after complete resection of high-risk stage III patients with melanoma (HR = 0.72 95.1% CI: 0.58, 0.88; p = 0.0013). Randomisation was stratified by tumour PD-L1 expression (≥ 5% vs. < 5%/indeterminate), and stage of disease per the AJCC staging system. Tumour assessments were conducted every 12 weeks for the first 2 years then every 6 months thereafter.
The primary endpoint was recurrence-free survival (RFS). Key secondary endpoint were OS and QoL.
RFS, assessed by investigator, was defined as the time between the date of randomisation and the date of first recurrence (local, regional, or distant metastasis), new primary melanoma, or death due to any cause, whichever occurred first.
Baseline characteristics were generally balanced between the two groups. The median age was 55 years (range: 18-86), 58% were men, and 95% were white. Baseline ECOG performance status score was 0 (90%) or 1 (10%). The majority of patients had AJCC Stage III disease (81%), and 19% had Stage IV. Forty-two percent of patients were BRAF V600 mutation positive, 45% were BRAF wild type; and for 13% BRAF status was unknown. Among patients with quantifiable tumour PD-L1 expression (> 5%), the distribution of patients was balanced across the treatment groups. Tumour PD-L1 expression was determined using the PD-L1 IHC 28-8 pharmDx assay.
Minimum follow-up was approximately 18 months. The trial demonstrated a statistically significant improvement in RFS for patients randomised to the nivolumab arm compared with the ipilimumab 10 mg/kg arm based on a pre-specified interim analysis. At the time the study reached its primary endpoint of RFS, the secondary endpoint of OS was not yet available and subjects continue to be monitored. RFS results are shown in Figure 1 and Table 9 (all randomised population).
RFS benefit was consistently demonstrated across subgroups, including tumour PD-L1 expression, BRAF status, and stage of disease.
Quality of life (QoL), was assessed by the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30, the EQ-5D utility index and visual analog scale (VAS). QoL with nivolumab remained stable and close to baseline values during treatment.

Previously untreated unresectable or metastatic melanoma - Opdivo monotherapy.

Randomised phase 3 study vs. dacarbazine (CA209066).

The safety and efficacy of nivolumab 3 mg/kg as monotherapy for the treatment of advanced (unresectable or metastatic) melanoma were evaluated in a phase 3, randomised, double-blind study (CA209066). The study included adult patients (18 years or older) with confirmed, treatment-naive, Stage III or IV BRAF wild-type melanoma and an ECOG performance-status score of 0 or 1. Patients with active autoimmune disease, ocular melanoma, or active brain or leptomeningeal metastases were excluded from the study.
A total of 418 patients were randomised to receive either nivolumab (n = 210) administered intravenously over 60 minutes at 3 mg/kg every 2 weeks or dacarbazine (n = 208) at 1000 mg/m2 every 3 weeks. Randomisation was stratified by tumour PD-L1 status and M stage (M0/M1a/M1b versus M1c). Treatment was continued as long as clinical benefit was observed or until treatment was no longer tolerated. Treatment after disease progression was permitted for patients who had a clinical benefit and did not have substantial adverse effects with the study drug, as determined by the investigator. Tumour assessments, according to the Response Evaluation Criteria in Solid Tumours (RECIST), version 1.1, were conducted 9 weeks after randomisation and continued every 6 weeks for the first year and then every 12 weeks thereafter. The primary efficacy outcome measure was overall survival (OS). Key secondary efficacy outcome measures were investigator-assessed progression free survival (PFS) and objective response rate (ORR).
Baseline characteristics were balanced between the two groups. The median age was 65 years (range: 18-87), 59% were men, and 99.5% were white. Most patients had ECOG performance score of 0 (64%) or 1 (34%). Sixty-one percent of patients had M1c stage disease at study entry. Seventy-four percent of patients had cutaneous melanoma, and 11% had mucosal melanoma; 35% of patients had PD-L1 positive melanoma (≥ 5% tumour cell membrane expression). Sixteen percent of patients had received prior adjuvant therapy; the most common adjuvant treatment was interferon (9%). Four percent of patients had a history of brain metastasis, and 37% of patients had a baseline LDH level greater than ULN at study entry.
The observed OS (Figure 2, Table 10) benefit was consistently demonstrated across subgroups of patients including baseline ECOG performance status, M stage, history of brain metastases, and baseline LDH level. Survival benefit was observed regardless of whether PD-L1 expression was above or below a PD-L1 tumour membrane expression cut-off of 5% or 10%.

Previously untreated unresectable or metastatic melanoma - Opdivo in combination with ipilimumab.

Randomised phase 3 study of nivolumab in combination with ipilimumab or nivolumab as monotherapy vs. ipilimumab as monotherapy (CA209067).

The safety and efficacy of nivolumab in combination with ipilimumab and nivolumab monotherapy for the treatment of advanced (unresectable or metastatic) melanoma were evaluated in a phase 3, randomised, double-blind study (CA209067). The study included adult patients (18 years or older) with confirmed unresectable Stage III or Stage IV melanoma, regardless of PD-L1 expression. Patients were to have ECOG performance status score of 0 or 1. Patients who had not received prior systemic anticancer therapy for unresectable or metastatic melanoma were enrolled. Prior adjuvant or neoadjuvant therapy was allowed if it was completed at least 6 weeks prior to randomisation. Patients with active autoimmune disease, ocular/uveal melanoma, or active brain or leptomeningeal metastases were excluded from the study.
A total of 945 patients were randomised to receive nivolumab in combination with ipilimumab (n = 314), nivolumab as monotherapy (n = 316), or ipilimumab as monotherapy (n = 315). Patients in the combination arm received nivolumab 1 mg/kg over 60 minutes and ipilimumab 3 mg/kg over 90 minutes administered intravenously every 3 weeks for the first 4 doses, followed by nivolumab 3 mg/kg as monotherapy every 2 weeks. Patients in the nivolumab monotherapy arm received nivolumab 3 mg/kg every 2 weeks. Patients in the comparator arm received ipilimumab 3 mg/kg and nivolumab-matched placebo intravenously every 3 weeks for 4 doses followed by placebo every 2 weeks. Randomisation was stratified by PD-L1 expression (≥ 5% vs. < 5% tumour cell membrane expression), BRAF status, and M stage per the American Joint Committee on Cancer (AJCC) staging system. Treatment was continued as long as clinical benefit was observed or until treatment was no longer tolerated. Tumour assessments were conducted 12 weeks after randomisation then every 6 weeks for the first year, and every 12 weeks thereafter. The co-primary outcome measures were PFS and OS. ORR and the duration of response were also assessed. This study evaluated whether PD-L1 expression was a predictive biomarker for the co-primary endpoints. The efficacy of nivolumab in combination with ipilimumab and nivolumab monotherapy was each compared with that of ipilimumab. In addition, the differences between the two Opdivo-containing groups were evaluated descriptively, but not included in formal hypothesis testing.
Baseline characteristics were balanced across the three treatment groups. The median age was 61 years (range: 18 to 90 years), 65% of patients were men, and 97% were white. ECOG performance status score was 0 (73%) or 1 (27%). The majority of the patients had AJCC Stage IV disease (93%); 58% had M1c disease at study entry. Twenty-two percent of patients had received prior adjuvant therapy. Thirty-two percent of patients had BRAF mutation-positive melanoma; 26.5% of patients had PD-L1 ≥ 5% tumour cell membrane expression. Four percent of patients had a history of brain metastasis, and 36% of patients had a baseline LDH level greater than ULN at study entry. Baseline tumour tissue specimens were systematically collected prior to randomisation in order to conduct planned analyses of efficacy according to PD-L1 expression. Quantifiable tumour PD-L1 expression was measured in 89% (278/314) of patients randomised to nivolumab in combination with ipilimumab, 91% (288/316) of patients randomised to nivolumab monotherapy, and 88% (277/315) of patients randomised to ipilimumab alone. Among patients with quantifiable PD-L1 expression, the distribution of patients was balanced across the three treatment groups at the predefined tumour PD-L1 expression level of ≥ 5% (24% in the nivolumab in combination with ipilimumab arm, 28% in the nivolumab monotherapy arm, and 27% in the ipilimumab arm). Tumour PD-L1 expression was determined using the PD-L1 IHC 28-8 pharmDx assay.
Both nivolumab-containing arms demonstrated a significant PFS and OS benefit and greater ORR compared with ipilimumab monotherapy.
Efficacy results for all randomised patients are shown in Table 11 and Figure 3 (PFS), and Figure 4 (OS).
Among 128 patients who discontinued nivolumab in combination with ipilimumab due to adverse reaction after 18 months of follow-up, median PFS was 16.7 months (95% CI: 10.2, NA). Among 131 patients who discontinued the combination due to adverse reaction after 28 months of follow-up, the ORR was 71% (93/131) with 20% (26/131) achieving a complete response and median OS was not reached.
The improvements in PFS, OS, ORR and DOR that were seen in both nivolumab-containing arms compared to ipilimumab monotherapy (Table 11) were consistent across patient subgroups including baseline ECOG performance status, BRAF status, M stage (7th Edition of AJCC melanoma of the skin staging classification system), age, history of brain metastases, baseline LDH level and tumour PD-L1 expression levels.
Greater objective response rates were demonstrated for nivolumab in combination with ipilimumab relative to nivolumab monotherapy across tumour PD-L1 expression levels, with a best overall response of complete response correlating to an improved survival rate.
Analyses comparing nivolumab monotherapy to nivolumab in combination with ipilimumab were all descriptive. Kaplan-Meier plots of these exploratory subgroup analyses comparing PFS and OS in patients with tumour PD-L1 expression of < 1% versus ≥ 1% are included (see Figure 5 and Figure 6).
No clear cut-off for PD-L1 expression can reliably be established when considering the relevant endpoints of tumour response, PFS and OS.
The safety of the combination of nivolumab and ipilimumab in patients across all pre-defined subgroups was consistent with that in all randomised patients.

Randomised phase 2 study of nivolumab in combination with ipilimumab vs ipilimumab (CA209069).

Study CA209069 was a randomised, Phase 2, double-blind study comparing the combination of nivolumab and ipilimumab with ipilimumab alone in 142 patients with advanced (unresectable or metastatic) melanoma with similar inclusion criteria to study CA209067 and the primary analysis in patients with BRAF wild-type melanoma (77% of patients). Investigator assessed ORR was 61% (95% CI: 48.9, 72.4) in the combination arm (n = 72) versus 11% (95% CI: 3.0, 25.4) for the ipilimumab arm (n = 37). The estimated 12 and 18 month OS rates were 79% (95% CI: 67, 87) and 73% (95% CI: 61, 82) respectively for the combination and 62% (95% CI: 44, 75) and 56% (95% CI: 39, 70) respectively for ipilimumab.

Previously treated unresectable or metastatic melanoma - Opdivo monotherapy.

Randomised phase 3 study vs. chemotherapy (CA209037).

The safety and efficacy of Opdivo 3 mg/kg as monotherapy for the treatment of advanced (unresectable or metastatic) melanoma were evaluated in a phase 3, randomised, open-label study (CA209037). The study included adult patients who had progressed on or after ipilimumab and if BRAF V600 mutation positive had also progressed on or after BRAF kinase inhibitor therapy. Patients with active autoimmune disease, ocular melanoma, or a known history of prior ipilimumab-related high-grade (grade 4 per CTCAE v4.0) adverse reactions except for resolved nausea, fatigue, infusion reactions, or endocrinopathies were excluded from the study.
A total of 405 patients were randomised to receive either nivolumab (n = 272) administered intravenously over 60 minutes at 3 mg/kg every 2 weeks or chemotherapy (n = 133) which consisted of the investigator's choice of either dacarbazine (1000 mg/m2 every 3 weeks) or carboplatin (AUC 6 every 3 weeks) and paclitaxel (175 mg/m2 every 3 weeks). Randomisation was stratified by BRAF and tumour PD-L1 status and best response to prior ipilimumab.
The co-primary efficacy outcome measures were confirmed ORR in the first 120 patients treated with nivolumab, as measured by independent radiology review committee (IRRC) using RECIST 1.1, and comparison of OS of nivolumab to chemotherapy. Additional outcome measures included duration and timing of response.
The median age was 60 years (range: 23-88). Sixty-four percent of patients were men and 98% were white. ECOG performance scores were 0 for 61% of patients and 1 for 39% of patients. The majority (75%) of patients had M1c stage disease at study entry. Seventy-three percent of patients had cutaneous melanoma and 10% had mucosal melanoma. The number of prior systemic regimen received was 1 for 27% of patients, 2 for 51% of patients, and > 2 for 21% of patients. Twenty-two percent of patients had tumours that tested BRAF mutation positive and 50% of patients had tumours that were considered PD-L1 positive. Sixty-four percent of patients had no prior clinical benefit (CR/PR or SD) on ipilimumab. Baseline characteristics were balanced between groups except for the proportions of patients who had a history of brain metastasis (19% and 13% in the nivolumab group and chemotherapy group, respectively) and patients with LDH greater than ULN at baseline (51% and 35%, respectively).
At the time of this final ORR analysis, results from 120 nivolumab-treated patients and 47 chemotherapy-treated patients who had a minimum of 6 months of follow-up were analysed. Efficacy results are presented in Table 12.
Objective responses to nivolumab (according to the definition of the co-primary endpoint) were observed in patients with or without BRAF mutation-positive melanoma. Of the patients who received nivolumab, the ORR in the BRAF mutation-positive subgroup (n = 26) was 23% (95% CI: 9.0, 43.6), and 34% (95% CI: 24.6, 44.5) in patients whose tumours were BRAF wild-type (n = 94). Objective responses to nivolumab were observed regardless of whether patients had tumours that were designated PD-L1 negative or PD-L1 positive (tumour membrane expression cut off of 5% or 10%). However, the role of this biomarker (tumour PD-L1 expression) has not been fully elucidated.
The OS data were not mature at the time of the PFS analysis. There was no statistically significant difference between nivolumab and chemotherapy in the preliminary OS analysis that was not adjusted for the potentially confounding effects of subsequent therapy. It is of note that 42 (31.6%) patients in the chemotherapy arm subsequently received an anti-PD1 treatment.
PFS numerically favoured the nivolumab group vs. the chemotherapy group in all randomised patients, BRAF mutation positive patients, and BRAF wild-type patients (HRs 0.74 [95% CI: 0.57, 0.97], 0.98 [95% CI: 0.56, 1.70], and 0.63 [95% CI: 0.47, 0.85], respectively).

Phase 1 dose-escalation study (CA209003/MDX1106-03).

The safety and tolerability of Opdivo were investigated in a phase 1, open-label dose-escalation study in various tumour types, including malignant melanoma. Of the 306 patients enrolled in the study, 107 had melanoma and received Opdivo at a dose of 0.1 mg/kg, 0.3 mg/kg, 1 mg/kg, 3 mg/kg, or 10 mg/kg for a maximum of 2 years. In this patient population, objective response was reported in 33 patients (31%) with a median duration of response of 22.9 months (95% CI: 17.0, NR). The median PFS was 3.7 months (95% CI: 1.9, 9.3). The median OS was 17.3 months (95% CI: 12.5, 36.7), and the estimated OS rates were 63% (95% CI: 53, 71) at 1 year, 48% (95% CI: 38, 57) at 2 years, and 41% (95% CI: 31, 51) at 3 years.

Non-small cell lung cancer (NSCLC).

Previously untreated advanced or metastatic NSCLC - Opdivo in combination with ipilimumab and chemotherapy.

Randomised phase 3 study vs. platinum-doublet chemotherapy (CA2099LA).

CA2099LA was a randomised, open-label trial in patients with metastatic or recurrent NSCLC. The trial included patients (18 years of age or older) with histologically confirmed Stage IV or recurrent NSCLC (per the 7th International Association for the Study of Lung Cancer classification [IASLC]), ECOG performance status 0 or 1, and no prior systemic anticancer therapy (including EGFR and ALK inhibitors) for metastatic disease. Patients were enrolled regardless of their tumor PD-L1 status. Patients with known EGFR mutations or ALK translocations sensitive to available targeted inhibitor therapy, untreated brain metastases, carcinomatous meningitis, active autoimmune disease, or medical conditions requiring systemic immunosuppression were excluded from the study. Patients with treated brain metastases were eligible if neurologically returned to baseline at least 2 weeks prior to enrollment, and either off corticosteroids, or on a stable or decreasing dose of < 10 mg daily prednisone equivalents.
Patients were randomized 1:1 to receive either nivolumab 360 mg administered intravenously over 30 minutes every 3 weeks in combination with ipilimumab 1 mg/kg administered intravenously over 30 minutes every 6 weeks and platinum-doublet chemotherapy administered every 3 weeks for 2 cycles; or platinum-doublet chemotherapy administered every 3 weeks for 4 cycles. Patients with non-squamous NSCLC in the control arm could receive optional pemetrexed maintenance therapy. Stratification factors for randomisation were tumour PD-L1 expression level (≥ 1% versus < 1% or non-quantifiable), histology (squamous versus non-squamous), and gender (male versus female). Platinum-doublet chemotherapy consisted of either:
carboplatin (AUC 5 or 6) and pemetrexed 500 mg/mg2; or cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 for non-squamous NSCLC; or
carboplatin (AUC 6) and paclitaxel 200 mg/m2 for squamous NSCLC.
Study treatment continued until disease progression, unacceptable toxicity, or for up to 2 years. Treatment continued beyond disease progression if a patient was clinically stable and was considered to be deriving clinical benefit by the investigator. Patients who discontinued combination therapy because of an adverse event attributed to ipilimumab were permitted to continue nivolumab as a single agent. Tumour assessments were performed every 6 weeks from the first dose of study treatment for the first 12 months, then every 12 weeks until disease progression or study treatment was discontinued. The primary efficacy outcome measure was OS. Additional efficacy outcome measures included PFS, ORR, and duration of response as assessed by BICR.
A total of 719 patients were randomized to receive either nivolumab in combination with ipilimumab and platinum-doublet chemotherapy (n=361) or platinum-doublet chemotherapy (n=358). The median age was 65 years (range: 26 to 86) with 51% of patients ≥ 65 years and 10% of patients ≥ 75 years. The majority of patients were white (89%) and male (70%). Baseline ECOG performance status was 0 (31%) or 1 (68%), 57% of patients had tumours with PD-L1expression ≥ 1% and 37% had tumours with PD-L1 expression < 1%, 31% had tumours with squamous histology and 69% had tumours with non-squamous histology, 17% had brain metastases and 86% were former or current smokers.
Efficacy results from the prespecified interim analysis when 351 events were observed (87% of the planned number of events for final analysis) demonstrated a statistically significant benefit in OS, PFS, and ORR, and a clinically meaningful benefit in duration of response (Table 13). With an additional 4.6 months of follow-up, the hazard ratio for overall survival was 0.66 (95% CI: 0.55, 0.80) and median survival was 15.6 months (95% CI: 13.9, 20.0) and 10.9 months (95% CI: 9.5, 12.5) for patients receiving nivolumab and ipilimumab and platinum-doublet chemotherapy or platinum-doublet chemotherapy, respectively (Figure 7).

Previously treated advanced or metastatic squamous (SQ) NSCLC - Opdivo monotherapy.

Randomised phase 3 study vs. docetaxel (CA209017).

The safety and efficacy of nivolumab 3 mg/kg as monotherapy for the treatment of advanced or metastatic SQ NSCLC were evaluated in a phase 3, randomised, open-label study (CA209017). The study included patients (18 years or older) who have experienced disease progression during or after one prior platinum doublet-based chemotherapy regimen. Patients were enrolled regardless of their PD-L1 status. Patients with active autoimmune disease, symptomatic interstitial lung disease, or untreated brain metastasis were excluded from the study. Patients with treated brain metastases were eligible if neurologically returned to baseline at least 2 weeks prior to enrolment, and either off corticosteroids, or on a stable or decreasing dose of < 10 mg daily prednisone equivalents.
A total of 272 patients were randomised to receive either nivolumab 3 mg/kg (n = 135) administered intravenously over 60 minutes every 2 weeks or docetaxel (n = 137) 75 mg/m2 every 3 weeks. Treatment was continued as long as clinical benefit was observed or until treatment was no longer tolerated.
Tumour assessments, according to the RECIST, version 1.1, were conducted 9 weeks after randomisation and continued every 6 weeks thereafter. The primary efficacy outcome measure was OS. Key secondary efficacy outcome measures were investigator-assessed ORR and PFS. In addition, symptom improvement and overall health status were assessed using the Lung Cancer Symptom Score (LCSS) average symptom burden index and the EQ-5D Visual Analogue Scale (EQ-VAS), respectively.
Baseline characteristics were generally balanced between the two groups. The median age was 63 years (range: 39-85) with 44% ≥ 65 years of age and 11% ≥ 75 years of age. The majority of patients were white (93%) and male (76%). Thirty-one percent had progressive disease reported as the best response to their most recent prior regimen and 45% received nivolumab within 3 months of completing their most recent prior regimen. Baseline ECOG performance status score was 0 (24%) or 1 (76%).
The observed OS benefit (Figure 8, Table 14) was consistently demonstrated across subgroups of patients. At the pre-defined PD-L1 tumour membrane expression cutoff levels of 1%, 5%, and 10%, similar survival was observed regardless of PD-L1 expression status.
Study CA209017 included a limited number of patients ≥ 75 years (11 in the nivolumab group and 18 in the docetaxel group). Nivolumab showed numerically less effect on OS (HR 1.85; 95% CI: 0.76, 4.51), PFS (HR 1.76; 95%-CI: 0.77, 4.05) and ORR (9.1% vs. 16.7%). Because of the small sample size, no definitive conclusions can be drawn from these data.
The rate of disease-related symptom improvement, as measured by LCSS, was similar between the nivolumab group (18.5%) and the docetaxel group (21.2%). The average EQ-VAS increased over time for both treatment groups, indicating better overall health status for patients remaining on treatment.
The OS rates at 24 months were 22.9% (95% CI: 16.2, 30.3) for nivolumab and 8.0% (95% CI: 4.3, 13.3) for docetaxel. The PFS rate at 24 months for nivolumab was 15.6% (95% CI: 9.7, 22.7) and for docetaxel there were no patients at risk at 24 months as all patients had either progressed, were censored, or lost to follow-up. With minimum 24 months follow-up, objective response rates remain 20.0% for nivolumab and 8.8% for docetaxel with median durations of response 25.2 months (range: 2.9, 30.4) and 8.4 months (range: 1.4+, 18.0+), respectively.

Single-arm phase 2 study (CA209063).

Study CA209063 was a single-arm, open-label study conducted in 117 patients with locally advanced or metastatic squamous NSCLC after two or more lines of therapy; otherwise similar inclusion criteria as study CA209017 were applied. Nivolumab 3 mg/kg showed an overall response rate of 14.5% (95% CI: 8.7,22.2%), a median OS of 8.21 months (95% CI: 6.05,10.9), and a median PFS of 1.87 months (95% CI 1.77, 3.15). The PFS was measured by RECIST, version 1.1. The estimated 1-year survival rate was 41%.

Previously treated advanced or metastatic non-squamous (NSQ) NSCLC - Opdivo monotherapy.

Randomised phase 3 study vs. docetaxel (CA209057).

The safety and efficacy of nivolumab 3 mg/kg as a single agent for the treatment of advanced or metastatic non-squamous NSCLC were evaluated in a phase 3, randomised, open-label study (CA209057). The study included patients (18 years or older) who have experienced disease progression during or after one prior platinum doublet-based chemotherapy regimen which may have included maintenance therapy and who had an ECOG performance status score of 0 or 1. An additional line of TKI therapy was allowed for patients with known EGFR mutation or ALK translocation. Patients were enrolled regardless of their PD-L1 status. Patients with active autoimmune disease, symptomatic interstitial lung disease, or untreated brain metastasis were excluded from the study. Patients with treated brain metastases were eligible if neurologically returned to baseline at least 2 weeks prior to enrolment, and either off corticosteroids, or on a stable or decreasing dose of < 10 mg daily prednisone equivalents.
A total of 582 patients were randomised to receive either nivolumab 3 mg/kg administered intravenously over 60 minutes every 2 weeks (n = 292) or docetaxel 75 mg/m2 every 3 weeks (n = 290). Treatment was continued as long as clinical benefit was observed or until treatment was no longer tolerated. Tumour assessments, according to the RECIST version 1.1, were conducted 9 weeks after randomisation and continued every 6 weeks thereafter. The primary efficacy outcome measure was OS. Key secondary efficacy outcome measures were investigator-assessed ORR and PFS. In addition, symptom improvement and overall health status were assessed using the LCSS average symptom burden index and the EQ-5D Visual Analogue Scale (EQ-VAS), respectively.
The median age was 62 years (range: 21 to 85) with 34% ≥ 65 years of age and 7% ≥ 75 years of age. The majority of patients were white (92%) and male (55%). Baseline ECOG performance status was 0 (31%) or 1 (69%). Seventy-nine percent of patients were former/current smokers.
The Kaplan-Meier curves for OS are shown in Figure 9.
The trial demonstrated a statistically significant improvement in OS for patients randomised to nivolumab as compared with docetaxel at the prespecified interim analysis when 413 events were observed (93% of the planned number of events for final analysis). Efficacy results are shown in Table 15.
The rate of disease-related symptom improvement, as measured by LCSS, was similar between the nivolumab group (17.8%) and the docetaxel group (19.7%). The average EQ-VAS increased over time for both treatment groups, indicating better overall health status for patients remaining on treatment.
The OS rates at 24 months were 28.7% (95% CI: 23.6, 34.0) for nivolumab and 15.8% (95% CI: 11.9, 20.3) for docetaxel. The PFS rates at 24 months were 11.9% (95% CI: 8.3, 16.2) for nivolumab and 1.0% (95% CI: 0.2, 3.3) for docetaxel. With minimum 24 months follow-up, objective response rates remain 19.2% for nivolumab and 12.4% for docetaxel with median durations of response 17.2 months (range: 1.8, 33.7+) and 5.6 months (range: 1.2+, 16.8), respectively.

Renal cell carcinoma (RCC).

Previously untreated advanced or metastatic RCC - Opdivo in combination with ipilimumab.

Randomised phase 3 study of nivolumab in combination with ipilimumab vs. sunitinib (CA209214).

The safety and efficacy of nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg for the treatment of advanced RCC was evaluated in a Phase 3, randomised, open-label study (CA209214). The study included patients (18 years or older) with previously untreated, advanced or metastatic renal cell carcinoma and Karnofsky performance status ≥ 70%. Prior adjuvant or neoadjuvant therapy was allowed if such therapy did not include an agent that targets vascular endothelial growth factor (VEGF) or VEGF receptors and recurrence occurred at least 6 months after the last dose of adjuvant or neoadjuvant therapy. The primary efficacy population includes those intermediate/poor risk patients with at least 1 or more of 6 prognostic risk factors as per the International Metastatic RCC Database Consortium (IMDC) criteria (less than one year from time of initial renal cell carcinoma diagnosis to randomization, Karnofsky performance status < 80%, haemoglobin less than the lower limit of normal, corrected calcium of greater than 10 mg/dL, platelet count greater than the upper limit of normal, and absolute neutrophil count greater than the upper limit of normal). This study included patients regardless of their tumour PD-L1 status. Patients with any history of or concurrent brain metastases, active autoimmune disease, or medical conditions requiring systemic immunosuppression were excluded from the study. Patients were stratified by (IMDC) prognostic score and region.
A total of 1096 patients were randomised in the trial, of which 847 patients had intermediate/poor-risk RCC and received either nivolumab 3 mg/kg (n = 425) administered intravenously over 60 minutes in combination with ipilimumab 1 mg/kg administered intravenously over 30 minutes every 3 weeks for 4 doses followed by nivolumab monotherapy 3 mg/kg every 2 weeks or sunitinib (n = 422) 50 mg daily, administered orally for 4 weeks followed by 2 weeks off, every cycle. Treatment was continued as long as clinical benefit was observed or until treatment was no longer tolerated. The first tumour assessments were conducted 12 weeks after randomisation and continued every 6 weeks thereafter for the first year and then every 12 weeks until progression or treatment discontinuation, whichever occurred later. Treatment beyond initial investigator-assessed RECIST, version 1.1-defined progression was permitted if the patient had a clinical benefit and was tolerating study drug as determined by the investigator. The primary efficacy outcome measures were OS, ORR and PFS as determined by a Blinded Independent Central Review (BICR) in intermediate/poor risk patients.
Baseline characteristics were generally balanced between the two groups. The median age was 61 years (range: 21-85) with 38% ≥ 65 years of age and 8% ≥ 75 years of age. The majority of patients were male (73%) and white (87%), and 31% and 69% of patients had a baseline KPS of 70 to 80% and 90 to 100%, respectively. The median duration of time from initial diagnosis to randomisation was 0.4 years in both the nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg and sunitinib groups. The median duration of treatment was 7.9 months (range: 1 day-21.4+ months) in nivolumab with ipilimumab-treated patients and was 7.8 months (range: 1 days-20.2+ months) in sunitinib-treated patients. Nivolumab with ipilimumab was continued beyond progression in 29% of patients.
The Kaplan-Meier curves for OS in intermediate/poor risk patients is shown in Figure 10.
The trial demonstrated superior OS and ORR and an improvement in PFS for intermediate/poor risk patients randomised to nivolumab plus ipilimumab as compared with sunitinib (Table 16 and Figure 11). OS benefit was observed regardless of tumour PD-L1 expression level.
Efficacy results are shown in Table 16.
The median time to onset of objective response was 2.8 months (range: 0.9-11.3 months) after the start of nivolumab with ipilimumab treatment. One hundred seventy-seven (41.6%) responders had ongoing responses with a duration ranging from 1.4+-25.5+ months.
Disease related symptoms, cancer symptoms and non-disease specific Quality of Life (QoL) were assessed as an exploratory endpoint using the FKSI-19, FACT-G, and EQ-5D scales. Fewer patients in the nivolumab in combination with ipilimumab arm reported symptom deterioration than in the sunitinib arm, and scores for QoL were greater for nivolumab in combination with ipilimumab patients vs. those in the sunitinib arm at each assessment during the first six months of the study, when completion rates exceeded 80%. As patients were not blinded to treatment, interpretation of these patient-reported outcomes is limited.

Previously treated advanced or metastatic RCC - Opdivo monotherapy.

Randomised phase 3 study of nivolumab vs everolimus (CA209025).

The safety and efficacy of nivolumab 3 mg/kg as a single agent for the treatment of advanced RCC was evaluated in a Phase 3, randomised, open-label study (CA209025). The study included patients (18 years or older) who have experienced disease progression during or after 1 or 2 prior anti-angiogenic therapy regimens and no more than 3 total prior systemic treatment regimens. Patients had to have a Karnofsky Performance Score (KPS) ≥ 70%. All patients had clear cell histology component. This study included patients regardless of their PD-L1 status. Patients with any history of or concurrent brain metastases, prior treatment with an mammalian target of rapamycin (mTOR) inhibitor, active autoimmune disease, or medical conditions requiring systemic immunosuppression were excluded from the study.
A total of 821 patients were randomised to receive either nivolumab 3 mg/kg (n = 410) administered intravenously over 60 minutes every 2 weeks or everolimus (n = 411) 10 mg daily, administered orally. Treatment was continued as long as clinical benefit was observed or until treatment was no longer tolerated. The first tumour assessments were conducted 8 weeks after randomisation and continued every 8 weeks thereafter for the first year and then every 12 weeks until progression or treatment discontinuation, whichever occurred later. Tumour assessments were continued after treatment discontinuation in patients who discontinued treatment for reasons other than progression. Treatment beyond initial investigator-assessed RECIST 1.1-defined progression was permitted if the patient had a clinical benefit and was tolerating study drug as determined by the investigator. The primary efficacy outcome measure was OS. Secondary efficacy assessments included investigator-assessed ORR and PFS.
Baseline characteristics were generally balanced between the two groups. The median age was 62 years (range: 18-88) with 40% ≥ 65 years of age and 9% ≥ 75 years of age. The majority of patients were male (75%) and white (88%), all Memorial Sloan Kettering Cancer Center (MSKCC) risk groups were represented, and 34% and 66% of patients had a baseline KPS of 70 to 80% and 90 to 100%, respectively. The majority of patients (72%) were treated with one prior anti-angiogenic therapy. The median duration of time from initial diagnosis to randomisation was 2.6 years in both the nivolumab and everolimus groups. The median duration of treatment was 5.5 months (range: 0 - 29.6+ months) in nivolumab-treated patients and was 3.7 months (range: 6 days-25.7+ months) in everolimus-treated patients.
Nivolumab was continued beyond progression in 44% of patients.
The Kaplan-Meier curves for OS are shown in Figure 11.
The trial demonstrated a statistically significant improvement in OS for patients randomised to nivolumab as compared with everolimus at the prespecified interim analysis when 398 events were observed (70% of the planned number of events for final analysis) (Table 17 and Figure 11). OS benefit was observed regardless of PD-L1 expression level.
Efficacy results are shown in Table 17.
The median time to onset of objective response was 3.5 months (range: 1.4-24.8 months) after the start of nivolumab treatment. Forty-nine (47.6%) responders had ongoing responses with a duration ranging from 0.0-27.6+ months.
Disease-related symptoms and non-disease specific quality of life (QoL) were assessed as a secondary endpoint using the Functional Assessment of Cancer Therapy-Kidney Symptom Index-Disease Related Symptoms (FKSI-DRS) and the EuroQoL EQ-5D scales. Patients in the nivolumab arm reported better symptom improvement and time to improvement than those in the everolimus arm. As patients were not blinded to treatment, interpretation of these patient-reported outcomes is limited.

Classical Hodgkin lymphoma (cHL).

Previously treated relapsed or refractory cHL - Opdivo monotherapy.

Single-arm phase 2 study (CA209205) and phase 1 dose escalation study (CA209039).

Two open-label studies evaluated the safety and efficacy of nivolumab 3 mg/kg as a single agent for the treatment of relapsed or refractory cHL following autologous stem cell transplantation (ASCT).
Study CA209205 is an ongoing Phase 2, open-label, multi-cohort, single-arm study of nivolumab in cHL. It includes 243 patients who had ASCT; Cohort A included 63 (26%) patients who were brentuximab vedotin naïve; Cohort B included 80 (33%) patients who had received brentuximab vedotin after ASCT failure; and Cohort C included 100 (41%) patients who had received brentuximab vedotin before and/or after ASCT out of which 33 (14%) patients received brentuximab vedotin only prior to ASCT. Study CA209039 was an open-label, multicentre, dose escalation Phase 1 study that included 23 patients with cHL, 15 of whom received nivolumab following ASCT and brentuximab vedotin treatment and 5 of whom were ASCT naive.
Both studies included patients regardless of their tumour PD-L1 status and excluded patients with ECOG performance status of 2 or greater, autoimmune disease, hepatic transaminases more than 3 times ULN, creatinine clearance less than 40 mL/min, prior allogeneic haematopoietic stem cell transplant (HSCT), chest irradiation within 24 weeks or symptomatic interstitial lung disease.
In both studies, patients received 3 mg/kg of Opdivo administered intravenously over 60 minutes every 2 weeks until disease progression or unacceptable toxicity (or maximal clinical benefit in CA209039). Dose reduction was not permitted. Tumour assessments were conducted 4 weeks (CA209039) or 9 weeks (CA209205) after the start of treatment and continued thereafter until disease progression or treatment discontinuation.
The primary efficacy outcome measure was Objective Response Rate (ORR). Additional efficacy measures included duration of response, PFS and OS. Data from post-ASCT patients in study CA209205 were pooled (Cohort A+B+C referred to as Combined Cohorts). The baseline and disease characteristics of the patients in each study were similar. In CA209205, the median age was 34 years with 7 subjects aged 65 years or older; 87% were white, 58% were male; 57.2% had Stage IV disease at study entry; the median number of prior systemic regimens was 4 (range 2 to 15); 84% had had a best response of CR or PR to regimen prior to ASCT. In CA209039, the median age was 35 years (range 20-54), 87% were white, the median number of prior systemic regimens was 5 (range 2 to 15).
Efficacy from both studies was evaluated by the same IRRC using the 2007 revised International Working Group criteria. Median duration of follow-up 22.7 months (range 1.9 to 27.2 months) in Cohort B in Study CA209205, 17.8 months (range 1.0 to 27.2 months) in the Combined Cohorts in Study CA209205 and 21.9 months (range 11.2 to 27.6 months) in study CA209039. Follow-up was ongoing at the time of data submission. Results are shown in Table 18.
PFS and OS were exploratory endpoints in these studies. The median PFS was 14.7 months (95% CI: 10.5, 19.6), 12.7 months (95% CI: 5.91, NA) and 14.7 months (11.3, 18.5) in CA209205 Cohort B, CA209039 and CA209205 combined Cohorts, respectively. The PFS rate at 12 months was 51% (95% CI 38, 62), 69% (95% CI 37, 88) and 51% (95% CI 44, 58) in CA209205 Cohort B, CA209039 and CA209205 combined Cohorts, respectively. At the time of database lock, OS data were immature and the median had not been reached in CA209205 and CA209039. The OS rate at 12 months was 95% (95% CI 87, 98), 93% (95% CI 61, 99) and 92% (CI 88, 95) in CA209205 Cohort B, CA209039 and CA209205 combined Cohorts, respectively.
Objective response per IRRC with nivolumab was observed regardless of baseline tumour PD-L1 expression status.
B-symptoms were present in 22% (53/243) of the patients in CA209205 at baseline. Nivolumab treatment resulted in rapid resolution of B-symptoms in 88.7% (47/53) of the patients, with a median time to resolution of 1.9 months.
Health related Quality of Life (QoL) was assessed in CA209205 using the patient reported EQ 5D VAS and EORTC-QLQ-C30 (overall health status). There was a high rate of completion up to Week 33 of treatment. During this time, mean EQ-5D VAS scores increased from baseline and EORTC QLQ-C30 scores remained stable.
Data from cHL patients 65 years of age or older are too limited to draw conclusions on this population.

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

Previously treated recurrent or metastatic SCCHN - Opdivo monotherapy.

Randomised phase 3 study vs. chemotherapy (CA209141).

The safety and efficacy of nivolumab 3 mg/kg as a single agent for the treatment of metastatic or recurrent SCCHN were evaluated in a phase 3, randomised, open-label study (CA209141). The study included patients (18 years or older) who have experienced disease progression during or within 6 months of receiving a prior platinum-based therapy regimen and had an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1. Prior platinum-based therapy was administered in either the adjuvant, neo-adjuvant, primary, recurrent or metastatic setting. Patients were enrolled regardless of their PD-L1 or human papilloma virus (HPV) status.
Patients with active autoimmune disease, medical conditions requiring immunosuppression, recurrent or metastatic carcinoma of the nasopharynx, squamous cell carcinoma of unknown primary histology, salivary gland or non-squamous histologies (e.g. mucosal melanoma), or untreated brain metastasis were excluded from the study. Patients with treated brain metastases were eligible if neurologically returned to baseline at least 2 weeks prior to enrolment, and either off corticosteroids, or on a stable or decreasing dose of < 10 mg daily prednisone equivalents.
A total of 361 patients were randomised to receive either nivolumab 3 mg/kg (n = 240) administered intravenously over 60 minutes every 2 weeks or investigator's choice of either cetuximab (n = 15), 400 mg/m2 loading dose followed by 250 mg/m2 weekly or methotrexate (n = 52) 40 to 60 mg/m2 weekly, or docetaxel (n = 54) 30 to 40 mg/m2 weekly. Randomisation was stratified by prior cetuximab treatment. Treatment was continued as long as clinical benefit was observed or until treatment was no longer tolerated. Tumour assessments, according to RECIST version 1.1, were conducted 9 weeks after randomisation and continued every 6 weeks thereafter. Treatment beyond initial investigator-assessed RECIST, version 1.1-defined progression was permitted in patients receiving nivolumab if the patient had a clinical benefit and was tolerating study drug as determined by the investigator. The primary efficacy outcome measure was OS. Key secondary efficacy outcome measures were investigator-assessed PFS and ORR.
Baseline characteristics were generally balanced between the two groups. The median age was 60 years (range: 28-83) with 31% ≥ 65 years of age and 5% ≥ 75 years of age, 83% were male, and 83% were white. Baseline ECOG performance status score was 0 (20%) or 1 (78%), 77% were former/current smokers, 90% had Stage IV disease, 66% had two or more lesions, 45%, 34% and 20% received 1, 2, or 3 or more prior lines of systemic therapy, respectively.
With a minimum follow-up of 11.4 months, the trial demonstrated a statistically significant improvement in OS for patients randomised to nivolumab as compared with investigator's choice.
The Kaplan-Meier curves for OS are shown in Figure 12. Efficacy results are shown in Table 19.
Patients with investigator-assessed primary site of oropharyngeal cancer were tested for HPV by p16 immunohistochemistry. OS benefit was observed regardless of p16 status (p16-positive status: HR = 0.63; 95% CI: 0.38, 1.04 and p16-negative status: HR = 0.64, 95% CI: 0.40, 1.03, and p16-unknown* HR = 0.78, (95% CI: 0.55, 1.10).
*Unknown includes patients with non-oropharyngeal cancer of the head and neck in whom HPV testing was not required.

Safety and efficacy in elderly patients.

No overall differences in safety or efficacy were reported between elderly (≥ 65 years) and younger patients (< 65 years). Data from SCCHN patients 75 years of age or older are too limited to draw conclusions on this population.

Urothelial carcinoma (UC).

Previously treated metastatic or unresectable UC - Opdivo monotherapy.

Two open-label studies evaluated the safety and efficacy of nivolumab 3 mg/kg as a single agent for the treatment of locally advanced or metastatic urothelial carcinoma.

Single-arm phase 2 study (CA209275).

The safety and efficacy of nivolumab 3 mg/kg as a single agent for the treatment of patients with locally advanced or metastatic urothelial carcinoma was evaluated in a phase 2, multicentre, open-label, single-arm study (CA209275).
The study included patients (18 years or older) who had disease progression during or following platinum-containing chemotherapy for advanced or metastatic disease or had disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. Patients had an ECOG performance status score of 0 or 1 and were enrolled regardless of their tumour PD-L1 status. Patients with active brain metastases or leptomeningeal metastases, active autoimmune disease, or medical conditions requiring systemic immunosuppression were excluded from the study.
Patients received nivolumab 3 mg/kg administered intravenously over 60 minutes every 2 weeks. Treatment was continued as long as clinical benefit was observed or until treatment was no longer tolerated. The first tumour assessments were conducted 8 weeks after the start of treatment and continued every 8 weeks thereafter up to 48 weeks, then every 12 weeks until disease progression or treatment discontinuation, whichever occurred later. Tumour assessments were continued after treatment discontinuation in patients who discontinued treatment for reasons other than progression. Treatment beyond initial investigator-assessed RECIST, version 1.1-defined progression was permitted if the patient had a clinical benefit, did not have rapid disease progression, and was tolerating study drug as determined by the investigator. The primary efficacy outcome measure was ORR as determined by Blinded Independent Central Review (BICR). Additional efficacy measures included duration of response, PFS and OS.
A total of 270 patients with a minimum follow-up of 21.3 months were evaluable for efficacy. The median age was 66 years (range: 38 to 90) with 55% ≥ 65 years of age and 14% ≥ 75 years of age. The majority of patients were white (86%) and male (78%). Baseline ECOG performance status was 0 (54%) or 1 (46%). See Table 20.
Objective response per IRRC with nivolumab was observed regardless of baseline tumour PD-L1 expression status.
In 77 patients who received prior systemic therapy only in the neoadjuvant or adjuvant setting, the ORR was 23.4% (95% CI: 14.5%, 34.4%).
Disease related and non-disease specific quality of life (QoL) was assessed using the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30, and the EuroQoL EQ-5D scales. Overall QoL scores remained stable while Global Health Status (GHS) based on the EORTC-QLQ-C30, continued to improve through week 49. EQ-5D VAS scores showed clinically relevant improvement in QoL by Week 9, with continued improvement through Week 49. While both scales showed no detriment, QoL data should be interpreted cautiously in the context of the single arm study design.

Single-arm phase 1/2 study (CA209032).

CA209032 was a phase 1/2 open-label multi-cohort study which included a cohort of 78 patients with similar inclusion criteria to study CA209275 treated with nivolumab monotherapy 3 mg/kg for urothelial carcinoma. At a minimum follow-up of 9 months, investigator-assessed confirmed ORR was 24.4% (95% CI: 15.3, 35.4). The median duration of response was not reached (range: 4.4-16.6+ months). The median OS was 9.7 months (95% CI:7.26, 16.16) and the estimated OS rates were 69.2% (CI: 57.7, 78.2) at 6 months and 45.6% (CI: 34.2, 56.3) at 12 months.

Hepatocellular carcinoma (HCC).

Previously treated advanced HCC - Opdivo monotherapy.

Single-arm phase 2 study of nivolumab (CA209040).

The safety and efficacy of nivolumab 3 mg/kg as a single agent for the treatment of advanced HCC in patients previously treated with sorafenib (patients had either progressed on or were intolerant to sorafenib) were evaluated in a 154-patient subgroup of a phase 2, open-label, multi-cohort study (CA209040) conducted in patients with advanced HCC.
Additional eligibility criteria included histologic confirmation of HCC and Child-Pugh Class A. The trial excluded patients with active autoimmune disease, brain metastasis, a history of hepatic encephalopathy, clinically significant ascites, infection with HIV, or active co-infection with hepatitis B virus (HBV) and hepatitis C virus (HCV) or HBV and hepatitis D virus (HDV); however, patients with only active HBV or HCV were eligible. Tumour assessments were conducted every 6 weeks for 48 weeks and every 12 weeks thereafter. The primary efficacy outcome measure was confirmed overall response rate (ORR), as determined by blinded independent central review (BICR) using RECIST version 1.1 and modified RECIST (mRECIST) for HCC. Duration of response (DOR) was also assessed.
A total of 154 patients received nivolumab 3 mg/kg monotherapy administered intravenously every 2 weeks until disease progression or unacceptable toxicity. This group consisted of 9 patients who were treated at a 3 mg/kg dose out of a dose-escalation cohort (n = 37), plus all 145 patients who were treated at a 3 mg/kg dose in a dose-expansion cohort. All 154 patients had been previously treated with sorafenib, and either had progressed on or were intolerant to it. The median age was 63 years (range: 19 to 81), 77% were male, and 46% were white. Across the population, 31% had active HBV infection, 21% had active HCV infection, and 49% had no evidence of active HBV or HCV. The aetiology for HCC was alcoholic liver disease in 18% and non-alcoholic liver disease in 6.5% of patients. Baseline ECOG performance status was 0 (65%) or 1 (35%). Child-Pugh class and score was A5 for 68%, A6 for 31%, and B7 for 1% of patients. Seventy one percent (71%) of patients had extrahepatic spread, 29% had macrovascular invasion, and 37% had alpha-fetoprotein (AFP) levels ≥ 400 microgram/L. Prior treatment history included surgical resection (66%), radiotherapy (24%), or locoregional treatment (58%). All patients had received prior sorafenib, of whom 36 (23%) were unable to tolerate sorafenib; h 19% of patients had received 2 or more prior systemic therapies.
The efficacy results after a minimum follow-up of 15 months are summarised in Table 21.

Immunogenicity.

As with all therapeutic proteins, there is a potential for an immunogenic response to nivolumab.

Nivolumab monotherapy.

In a pooled analysis of 2022 patients who were treated with nivolumab 3 mg/kg every 2 weeks and were evaluable for the presence of anti-product antibodies, 231 patients (11.4%) tested positive for treatment emergent anti-product antibodies by an electrochemiluminescent (ECL) assay. Two (0.1%) patients were persistently positive. Neutralising antibodies were detected in only 15 (0.7% of the total) of the positive anti-product antibody patients. There was no evidence of altered pharmacokinetic profile, or toxicity profile associated with anti-product antibody development. Neutralising antibodies were not associated with loss of efficacy.

Nivolumab in combination with ipilimumab.

Of the patients who were treated with nivolumab in combination with ipilimumab and were evaluable for the presence of anti-nivolumab antibodies, the incidence of anti-nivolumab antibodies was 26.0% with nivolumab 3 mg/kg and ipilimumab 1 mg/kg every 3 weeks and 37.8% with nivolumab 1 mg/kg and ipilimumab 3 mg/kg every 3 weeks. Of the patients who were treated with nivolumab 360 mg every 3 weeks in combination with ipilimumab 1 mg/kg every 6 weeks and platinum-doublet chemotherapy and evaluable for the presence of anti-nivolumab antibodies, the incidence of anti-nivolumab antibodies was 33.8%. The incidence of neutralising antibodies against nivolumab was 0.5% with nivolumab 3 mg/kg and ipilimumab 1 mg/kg every 3 weeks, 4.6% with nivolumab 1 mg/kg and ipilimumab 3 mg/kg every 3 weeks and 2.6% with nivolumab 360 mg in combination with ipilimumab 1 mg/kg and platinum-doublet chemotherapy. Of the patients who were treated with nivolumab in combination with ipilimumab and evaluable for the presence of anti-ipilimumab antibodies, the incidence of anti-ipilimumab antibodies ranged from 6.3 to 8.4% and neutralising antibodies against ipilimumab ranged from 0 to 0.3%. There was no evidence of altered toxicity profile associated with anti-product antibody development. Neutralising antibodies were not associated with loss of efficacy.

5.2 Pharmacokinetic Properties

Nivolumab pharmacokinetics (PK) was assessed using a population PK approach for both single-agent nivolumab and nivolumab in combination with ipilimumab.

Nivolumab monotherapy.

The pharmacokinetics (PK) of nivolumab is linear in the dose range of 0.1 to 10 mg/kg. The exposure to nivolumab increased dose proportionally over the dose range of 0.1 to 10 mg/kg administered every 2 weeks.
Nivolumab clearance (CL) decreases over time, with a mean maximal reduction (% coefficient of variation [CV%]) from baseline values of 26% (32.6%) resulting in a geometric mean steady-state clearance (CLss) (CV%) of 7.91 mL/h (46%) in patients with metastatic tumours; the decrease in CLss is not considered clinically relevant. Nivolumab clearance does not decrease over time in patients with completely resected melanoma, as the geometric mean population clearance is 24% lower in this patient population compared with patients with metastatic melanoma at steady state. The geometric mean volume of distribution at steady state (Vss) (CV%) is 6.6 L (24.4%) and geometric mean elimination half-life (t1/2) is 25 days (55.4%). Steady-state concentrations of nivolumab were reached by 12 weeks when administered at 3 mg/kg every 2 weeks, and systemic accumulation was approximately 3-fold.
Nivolumab CL increased with increasing body weight. Body weight normalised dosing produced approximately uniform steady-state trough concentration over a wide range of body weights (34-162 kg).
The metabolic pathway of nivolumab has not been characterised. As a fully human IgG4 monoclonal antibody, nivolumab is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG.
Nivolumab baseline CL in adjuvant melanoma patients was approximately 40% lower and steady state CL approximately 20% lower relative to advanced melanoma. With available safety data, this decreases in CL were not clinically meaningful.
In patients with cHL, nivolumab CL was lower resulting in a 15 day increase in the half-life and a 43% increase in exposure (as measured by median Cavgss). The lower nivolumab CL was not considered clinically meaningful; there was a flat predicted exposure-response relationship.

Nivolumab in combination with ipilimumab.

When nivolumab 1 mg/kg was administered in combination with ipilimumab 3 mg/kg, the CL of nivolumab was increased by 29% and the CL of ipilimumab was increased by 9%, which was not considered clinically relevant. When nivolumab 3 mg/kg every 2 weeks was administered in combination with ipilimumab 1 mg/kg, the CL of nivolumab was increased by 17% and the CL of ipilimumab was increased by 18%, which were not considered clinically relevant.
When administered in combination with ipilimumab, the CL of nivolumab increased by 20% in the presence of anti-nivolumab antibodies and the CL of ipilimumab increased by 5.7% in the presence of anti-ipilimumab antibodies. These changes were not considered clinically relevant.
When nivolumab 360 mg every 3 weeks was administered in combination with ipilimumab 1 mg/kg every 6 weeks and chemotherapy, the CL of nivolumab decreased approximately 10% compared to nivolumab administered alone and the CL of ipilimumab increased approximately 22% compared to ipilimumab administered alone.

Special populations.

Population PK analysis suggested no difference in CL of nivolumab based on age, gender, race, solid tumour type, tumour size, and hepatic impairment. The majority of patients in this analysis were diagnosed with NSCLC. Although ECOG status, baseline glomerular filtration rate (GFR) and body weight had an effect on nivolumab CL, the effect was not clinically meaningful.
Patients with lower baseline serum albumin tended to have lower exposure to nivolumab. However, because of the flat exposure-response relationship between nivolumab exposure and overall survival, this effect is unlikely to be clinically meaningful and no dose adjustment is recommended for patients with lower serum albumin.

Renal impairment.

The effect of renal impairment on the CL of nivolumab was evaluated in patients with mild* (n = 1399), moderate* (n = 651), or severe* (n = 6) renal impairment compared to patients with normal* renal function (n = 1354) in population PK analyses. No clinically important differences in the CL of nivolumab were found between patients with mild or moderate renal impairment and patients with normal renal function. There were insufficient data to determine the effect of severe renal impairment on the CL of nivolumab (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use).
*Per National Kidney Foundation criteria of renal impairment: Normal: GFR ≥ 90 mL/min/1.73 m2; Mild: GFR < 90 and ≥ 60 mL/min/1.73 m2; Moderate: GFR < 60 and ≥ 30 mL/min/1.73 m2; Severe: GFR < 30 and ≥ 15 mL/min/1.73 m2.

Hepatic impairment.

The effect of hepatic impairment on the CL of nivolumab was evaluated in patients with mild* hepatic impairment (n = 351) and in patients with moderate* hepatic impairment (n = 10) compared to patients with normal* hepatic function (n = 3096) in the population PK analyses. No clinically important differences in the CL of nivolumab were found between patients with mild/moderate hepatic impairment and patients with normal hepatic function, although the number of patients with moderate hepatic impairment was limited. Nivolumab has not been studied in patients with severe* hepatic impairment (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use).
*Per National Cancer Institute criteria of hepatic dysfunction: Normal: total bilirubin and AST ≤ ULN; Mild: total bilirubin > 1.0 to 1.5 times ULN or AST > ULN; Moderate: total bilirubin > 1.5 to 3 times ULN and any AST; Severe: total bilirubin > 3 times ULN and any AST.

Cardiac electrophysiology.

The potential effect of nivolumab on QTc interval was evaluated in 146 patients at doses up to 10 mg/kg every three weeks. No changes in mean QT interval were detected in nivolumab-treated patients based on Fridericia correction method.
Ipilimumab did not have a clinically meaningful effect on the QTc interval at doses up to 10 mg/kg. Thus, QT interval prolongation is not expected with the nivolumab and ipilimumab combination.

5.3 Preclinical Safety Data

The effects of Opdivo on prenatal and postnatal development were evaluated in monkeys that received Opdivo at 10 and 50 mg/kg twice weekly from the onset of organogenesis in the first trimester through delivery, at exposure levels 8 and 35 times, respectively, those observed at the clinical dose of 3 mg/kg of Opdivo (based on AUC). There was a dose-dependent increase in foetal losses and increased neonatal mortality mainly in the 3rd trimester of pregnancy and after birth.
The remaining offspring of Opdivo-treated females survived to scheduled termination, with no treatment-related clinical signs, alterations to normal development, organ-weight effects, or gross and microscopic pathology changes. Results for growth indices, as well as teratogenic, neurobehavioral, immunological and clinical pathology parameters throughout the 6-month postnatal period were comparable to the control group.

Genotoxicity.

Studies to evaluate the genotoxic potential of Opdivo have not been performed.

Carcinogenicity.

Studies to evaluate the carcinogenic potential of Opdivo have not been performed.

6 Pharmaceutical Particulars

6.1 List of Excipients

Sodium citrate dihydrate, sodium chloride, mannitol (E421), pentetic acid (diethylenetriaminepentaacetic acid), polysorbate 80, sodium hydroxide (for pH-adjustment), hydrochloric acid (for pH-adjustment), water for injections.
This medicinal product does not contain any preservatives.

6.2 Incompatibilities

Opdivo should not be infused concomitantly in the same intravenous line with other medicinal products.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the ARTG. The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store in a refrigerator (2°C to 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.
After opening:
To reduce microbiological hazard, once opened, the medicinal product should be infused immediately.
After preparation of infusion: The administration of the Opdivo infusion must be completed within 24 hours of preparation. If not used immediately, the solution may be stored under refrigeration conditions: 2°-8°C and protected from light for up to 24 hours (a maximum of 8 hours of the total 24 hours can be at room temperature 20°-25°C and room light - the maximum 8 hour period under room temperature and room light conditions should be inclusive of the product administration period).
This medicinal product does not contain any preservatives.

6.5 Nature and Contents of Container

40 mg of nivolumab in 4 mL of concentrate solution for infusion is supplied in a 10 mL vial (Type I glass) with a stopper (coated butyl rubber) and an aluminium dark blue "flip off" seal. Pack of 1 vial containing 4 mL.
100 mg of nivolumab in 10 mL of concentrate solution for infusion is supplied in a 10 mL vial (Type I glass) with a stopper (coated butyl rubber) and an aluminium grey "flip off" seal. Pack of 1 vial containing 10 mL.
240 mg of nivolumab in 10 mL of concentrate solution for infusion is supplied in a 25 mL vial (Type I glass) with a stopper (coated butyl rubber) and an aluminium red "flip off" seal. Pack of 1 vial containing 24 mL.
Not all presentations may be available.

6.6 Special Precautions for Disposal

Each vial of Opdivo is for single use in one patient only. Discard any residue.
In Australia, any unused medicinal product or waste material should be discarded in accordance with local requirements.

6.7 Physicochemical Properties

CAS number.

CAS: 946414-94-4.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

Summary Table of Changes